Members of this protein family are found in genomic regions associated with conjugative transfer and integrated TOL-like plasmids. The specific function is unknown.
The antenna complexes of photosynthetic bacteria function as light-harvesting systems that absorb light and transfer the excitation energy to the reaction centres. The antenna complexes usually comprise 2 polypeptides (alpha- and beta-chains), 2-3 bacteriochlorophyll molecules and some carotenoids [
,
].The alpha- and beta-chains are small proteins of 40-70 residues. Each has an N-terminal hydrophilic cytoplasmic domain, a single transmembrane (TM) region, and a small C-terminal hydrophilic periplasmic domain. In both chains, the TM domain houses a conserved His residue, presumed to be involved in binding the magnesium atom of a bacteriochlorophyll group. The beta-chains are characterised by a further histidine at the C-terminal extremity of the cytoplasmic domain, which is also thought to be involved in bacteriochlorophyll binding.
This family represents the Light-harvesting protein B (also known as Antenna pigment protein) beta chain.
The cell envelope of Gram-negative bacteria consists of an inner (IM) and an outer membrane (OM) separated by an aqueous compartment, the periplasm, which contains the peptidoglycan layer. The OM is an asymmetric bilayer, with phospholipids in the inner leaflet and lipopolysaccharides (LPS) facing outward [
,
]. The OM is an effective permeability barrier that protects the cells from toxic compounds, such as antibiotics and detergents, thus allowing bacteria to inhabit several different and often hostile environments. LPS is responsible for the permeability properties of the OM. LPS consists of the lipid A moiety (a glucosamine-based phospholipid) linked to the short core oligosaccharide and the distal O-antigen polysaccharide chain. The core oligosaccharide can be further divided into an inner core, composed of 3-deoxy-D-mannooctulosanate (KDO) and heptose, and an outer core, which has a somewhat variable structure. LPS is essential in most Gram-negative bacteria, with the notable exception of Neisseria meningitidis. The biogenesis of the OM implies that the individual components are transported from the site of synthesis to their final destination outside the IM by crossing both hydrophilic and hydrophobic compartments. The machinery and the energy source that drive this process are not yet fully understood. The lipid A-core moiety and the O-antigen repeat units are synthesized at the cytoplasmic face of the IM and are separately exported via two independent transport systems, namely, the O-antigen transporter Wzx (RfbX) [,
] and the ATP binding cassette (ABC) transporter MsbA that flips the lipid A-core moiety from the inner leaflet to the outer leaflet of the IM [,
,
]. O-antigen repeat units are then polymerised in the periplasm by the Wzy polymerase and ligated to the lipid A-core moiety by the WaaL ligase [see, ,
].The LPS transport machinery is composed of LptA, LptB, LptC, LptD, LptE. This supported by the fact, that depletion of any of one of these proteins blocks the LPS assembly pathway and results in very similar OM biogenesis defects. Moreover, the location of at least one of these five proteins in every cellular compartment suggests a model for how the LPS assembly pathway is organised and ordered in space [
].LptA is required for the translocation of lipopolysaccharide (LPS) from the inner membrane to the outer membrane. May act as a chaperone that facilitates LPS transfer across the aquaeous environment of the periplasm. Interacts specifically with the lipid A domain of LPS [
,
,
].
Ectoine/hydroxyectoine ABC transporter, ATP-binding protein
Type:
Family
Description:
Members of this entry represent the ATP-binding protein of a conserved four-gene ABC transporter operon found next to ectoine utilisation operons and ectoine biosynthesis operons.Ectoine is a compatible solute that protects enzymes from high osmolarity. It is released by some species in response to hypoosmotic shock, and it is taken up by a number of bacteria as a compatible solute or for consumption. This entry shows strong sequence similarity to a number of amino acid ABC transporter ATP-binding proteins.ABC transporters belong to the ATP-Binding Cassette (ABC) superfamily, which uses the hydrolysis of ATP to energise diverse biological systems. ABC transporters minimally consist of two conserved regions: a highly conserved ATP binding cassette (ABC) and a less conserved transmembrane domain (TMD). These can be found on the same protein or on two different ones. Most ABC transporters function as a dimer and therefore are constituted of four domains, two ABC modules and two TMDs.ABC transporters are involved in the export or import of a wide variety of substrates ranging from small ions to macromolecules. The major function of ABC import systems is to provide essential nutrients to bacteria. They are found only in prokaryotes and their four constitutive domains are usually encoded by independent polypeptides (two ABC proteins and two TMD proteins). Prokaryotic importers require additional extracytoplasmic binding proteins (one or more per systems) for function. In contrast, export systems are involved in the extrusion of noxious substances, the export of extracellular toxins and the targeting of membrane components. They are found in all living organisms and in general the TMD is fused to the ABC module in a variety of combinations. Some eukaryotic exporters encode the four domains on the same polypeptide chain [
].The ABC module (approximately two hundred amino acid residues) is known to bind and hydrolyse ATP, thereby coupling transport to ATP hydrolysis in a large number of biological processes. The cassette is duplicated in several subfamilies. Its primary sequence is highly conserved, displaying a typical phosphate-binding loop: Walker A, and a magnesium binding site: Walker B. Besides these two regions, three other conserved motifs are present in the ABC cassette: the switch region which contains a histidine loop, postulated to polarise the attaching water molecule for hydrolysis, the signature conserved motif (LSGGQ) specific to the ABC transporter, and the Q-motif (between Walker A and the signature), which interacts with the gamma phosphate through a water bond. The Walker A, Walker B, Q-loop and switch region form the nucleotide binding site [,
,
].The 3D structure of a monomeric ABC module adopts a stubby L-shape with two distinct arms. ArmI (mainly β-strand) contains Walker A and Walker B. The important residues for ATP hydrolysis and/or binding are located in the P-loop. The ATP-binding pocket is located at the extremity of armI. The perpendicular armII contains mostly the alpha helical subdomain with the signature motif. It only seems to be required for structural integrity of the ABC module. ArmII is in direct contact with the TMD. The hinge between armI and armII contains both the histidine loop and the Q-loop, making contact with the gamma phosphate of the ATP molecule. ATP hydrolysis leads to a conformational change that could facilitate ADP release. In the dimer the two ABC cassettes contact each other through hydrophobic interactions at the antiparallel β-sheet of armI by a two-fold axis [
,
,
,
,
,
].The ATP-Binding Cassette (ABC) superfamily forms one of the largest of all protein families with a diversity of physiological functions [
]. Several studies have shown that there is a correlation between the functional characterisation and the phylogenetic classification of the ABC cassette [,
]. More than 50 subfamilies have been described based on a phylogenetic and functional classification [,
,
].
Members of this protein family include protein C, a non-structural protein of the operon for methyl coenzyme M reductase [
]. The function of this protein is unknown []. Other uncharacterised archaeal family members may be linked to methanogenesis or a process closely connected to it.
Uncharacterised conserved protein UCP019164, methanogenesis
Type:
Family
Description:
Members of this protein family, to date, are found in a completed prokaryotic genome if, and only if, the species is one of the archaeal methanogens. The exact function is unknown, but likely is linked to methanogenesis or a process closely connected to it.
Members of this protein family are protein C, a non-structural protein, of the operon for methyl coenzyme M reductase [
], also called coenzyme-B sulfoethylthiotransferase (). That enzyme, with alpha, beta, and gamma subunits, catalyzes the last step in methanogenesis; it has several modified sites, so accessory proteins are expected. Several methanogens have encode two such enzymes, designated I and II; this protein occurs only operons of type I. The precise function is unknown [
].
This entry represents a family of prokaryotic proteins with unknown function. They contain a number of highly conserved polar residues that could suggest an enzymatic activity.
CRISPR-associated protein GSU0052/csb3, Dpsyc system
Type:
Family
Description:
This entry represents a CRISPR-associated (cas) protein unique to the Dpsyc subtype (named for Desulfotalea psychrophila), although not universal to the that subtype. Members of this family occur in CRISPR loci of Geobacter sulfurreducens PCA, Gemmata obscuriglobus UQM 2246, Rhodospirillum centenum SW, Planctomyces limnophilus DSM 3776, and Methylosinus trichosporium OB3b.
Protein arginine methyltransferase NDUFAF7 superfamily
Type:
Homologous_superfamily
Description:
NDUFAF7 (NADH:ubiquinone oxidoreductase complex assembly factor 7), also known as MidA or mitochondrial protein midA homologue, plays a role in mitochondrial complex I activity [
].
Protein translocase subunit SecA, Actinobacteria-type
Type:
Family
Description:
Members of this family are the SecA subunit of the Mycobacterial type of accessory secretory system. This family is quite different to SecA of the Staph/Strep type [
].
Staphylococcal protein Ebh (extracellular matrix-binding protein homolog) is a giant protein, sometimes over 10,000 amino acids long [
,
]. Ebh from Staphylococcus aureus promotes bacterial attachment to both soluble and immobilised forms of fibronectin (Fn), in a dose-dependent and saturable manner [
]. This entry represents a non-repetitive amino-terminal domain of about 2400 amino acids found in Ebh proteins.
RPL6 contains a KOW motif and has an extra ribosomal role regulating the DNA damage response [
]. KOW domain is known as an RNA-binding motif that is shared so far among some families of ribosomal proteins, the essential bacterial transcriptional elongation factor NusG, the eukaryotic chromatin elongation factor Spt5, the higher eukaryotic KIN17 proteins and Mtr4 [].
Uncharacterised protein family Ycf55, cyanobacteria
Type:
Family
Description:
This entry represents proteins annotated as Ycf55. It is found encoded in the chloroplast genomes of algae, it is also found in plants and in the cyanobacteria. The function is unknown, though there are two completely conserved residues (L and D) that may be functionally important. As the family is exclusively found in the cyanobacteria and it may play a role in photosynthesis. Some members of this family are predicted to be response regulators because they contain an N-terminal CheY-like receiver domain.
Two-pore segment channels (TPCs or TPCNs) are located in membranes of acidic intracellular organelles (such as endo-lysosomes and plant vacuoles) and contain two putative pore-forming repeats. Each of these repeats contains six transmembrane segments and an intervening pore-loop, an architecture featured in voltage-gated channels [
]. Functional TPC channels are assembled from two TPC protein subunits forming a pore that conducts mainly Ca2 and Na. TPCs exist as three isoforms (TPC1-3): TPC1 and TPC2 are the most universal isoforms since TPC3 is absent from the genomes of many animals including those of human, mice, rats and flies []. This entry represents TPC1 from animals [
,
]. TPC1 was first identified as an NAADP (nicotinic acid adenine dinucleotide phosphate)-regulated Ca2+ channel. Later it was shown to serve as a voltage-gated highly-selective Na+ channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate) that senses pH changes and confers electrical excitability to organelles [,
,
,
,
].
The intermembrane space protein MIX23, also known as Caffeine-induced death protein 2 (Cid2), regulates or stabilises the mitochondrial protein import machinery and is specifically up-regulated under stress conditions. It is critical for the efficient import of proteins into the mitochondrial matrix, particularly if the function of the translocase of the inner membrane 23 is compromised. This entry includes MIX23 from S. cerevisiae and related fungal proteins [
].
Ribonuclease P (Rnp) is a ubiquitous ribozyme that catalyzes a Mg2 -dependent hydrolysis to remove the 5'-leader sequence of precursor tRNA (pre-tRNA) in all three domains of life [
]. In bacteria, the catalytic RNA (typically ~120kDa) is aided by a small protein cofactor (~14kDa) []. Archaeal and eukaryote RNase P consist of a single RNA and archaeal RNase P has four or five proteins, while eukaryotic RNase P consists of 9 or 10 proteins. Eukaryotic and archaeal RNase P RNAs cooperatively function with protein subunits in catalysis [].Eukaryotic nuclear RNase P shares most of its protein components with another essential RNP enzyme, nucleolar RNase MRP [
]. RNase MRP (mitochondrial RNA processing) is an rRNA processing enzyme that cleaves various RNAs, including ribosomal, messenger, and mitochondrial RNAs. It can cleave a specific site within precursor rRNA to generate the mature 5'-end of 5.8S rRNA []. Despite its name, the vast majority of RNase MRP is localized in the nucleolus []. RNase MRP has been shown to cleave primers for mitochondrial DNA replication and CLB2 mRNA. In yeast, RNase MRP possesses one putatively catalytic RNA and at least 9 protein subunits (Pop1, Pop3-Pop8, Rpp1, Snm1 and Rmp1) []. Human RNase MRP complex consists of 267 nucleotides and supports the interaction with and among at least seven protein components: hPop1, hPop5, Rpp20, Rpp25, Rpp30, Rpp38, and Rpp40) and three additional proteins, hPop4, Rpp21 and Rpp14, have been reported to be associated with at least a subset of RNase MRP complexes [].This entry represents the Pop5 from eukaryotes and related proteins from archaea.
This entry is designated stage II sporulation protein R. A comparative genome analysis of all sequenced genomes of Firmicutes shows that the proteins are strictly conserved among the sub-set of endospore-forming species. SpoIIR is a signalling protein that links the activation of sigma E to the transcriptional activity of sigma F during sporulation [
,
].
This entry describes stage V sporulation protein AC; a paralog of stage V sporulation protein AE. Both are proteins found to be present in a species, if and only if, that species is one of the Firmicutes capable of endospore formation, as of the time of the publication of the genome of Carboxydothermus hydrogenoformans. Mutants in spoVAC have a stage V sporulation defect.
This entry describes stage V sporulation protein AE; a paralog of stage V sporulation protein AC. Both are proteins found to be present in a species, if and only if, that species is one of the Firmicutes capable of endospore formation, as of the time of the publication of the genome of Carboxydothermus hydrogenoformans. Mutants in spoVAE have a stage V sporulation defect.
This entry represents the stage IV sporulation protein A (
), an ATPase that has a role at an early stage in the morphogenesis of the spore coat and is required for proper coat localisation to the forespore [
,
,
]. A comparative genome analysis of all sequenced genomes of Firmicutes shows that the proteins are strictly conserved among the subset of endospore-forming species. This protein contains an ATPase domain at the N-terminal, a structural middle domain and a C-terminal domain that is key for targeting SpoIVA to the outer forespore membrane [].
Proteins in this entry include the stage III sporulation protein AA that is encoded by one of several genes in the spoIIIA locus. This protein is only found in species that are capable of endospore formation.
Uncharacterised conserved protein UCP028137, membrane
Type:
Family
Description:
There is currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function. However, they are predicted to be integral membrane proteins (with several transmembrane segments).
Members of this protein family are stage V sporulation protein T (SpoVT), a protein of the sporulation/germination program in Bacillus subtilis and related species. The amino-terminal 50 amino acids are nearly perfectly conserved across all endospore-forming bacteria. SpoVT is a DNA-binding transcriptional regulator related to AbrB [
].
Members of this entry represent the uncharacterised protein SpoIIIAD, part of the spoIIIA operon that acts at sporulation stage III as part of a cascade of events leading to endospore formation. The operon is regulated by sigmaG [
]. Note that the start sites of members of this family as annotated tend to be variable; quite a few members have apparent homologous protein-coding regions continuing upstream of the first available start codon.
This entry represents the CUE domain found at the N terminus of N4BP2.
N4BP2 has been identified as BCL-3-binding protein (B3BP), a protein that interacts with the bcl-3 gene product and participates in connecting transcriptional activation and genetic recombination of the Ig gene []. In addition to BCL-3, it also interacts with p300/CBP histone acetyltransferases. N4BP2 shows intrinsic ATP binding and hydrolyzing activity. It contains an N-terminal ATP-binding region that is responsible for the interaction with BCL-3 and p300/CBP. N4BP2 also functions as a 5'-polynucleotide kinase that can transfer a phosphate group to the 5' end of DNA and RNA substrates. Moreover, N4BP2 contains a C-terminal MutS-related domain that possesses nicking endonuclease activity and may play a role in DNA mismatch repair (MMR) [].
This entry represents a domain found in the MmpL family of membrane transport proteins. Many of the proteins contain two copies of this aligned region. Some members have been characterised, for instance, Mycobacterium tuberculosis MMPL10 is required for the biosynthesis of polyacyltrehalose (PAT) and the transport of diacyltrehalose (DAT) and possibly PAT to the cell surface [
], while MMPL4 is a part of an export system required for biosynthesis and secretion of siderophores [].
ERp29 (also known as ERp28 and ERp31) is a ubiquitously expressed endoplasmic reticulum protein found in mammals [
]. This protein has an N-terminal thioredoxin-like domain, which is homologous to the domain of human protein disulphide isomerase (PDI). ERp29 may help mediate the chaperone function of PDI. The C-terminal Erp29 domain has a 5-helical bundle fold. ERp29 is thought to form part of the thyroglobulin folding complex []. The Drosophila homologue, Wind, is the product of windbeutel, an essential gene in the development of dorsal-ventral patterning. Wind is required for correct targeting of Pipe, a Golgi-resident type II transmembrane protein with homology to 2-O-sulfotransferase. The C-terminal domain of Wind is thought to provide a distinct site required for interaction with its substrate, Pipe [
].
The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [
].Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca
2+to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K
+concentration [
].The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [
,
].Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM
domains, with two extracellular and three cytoplasmic regions. This modelhas been validated for several of the family members by
in vitrobiochemical
analysis. Both N- and C-termini are thought to face the cytoplasm, and thethird TM domain has an amphipathic character, suggesting that it contributes
to the lining of the formed-channel. Amino acid sequence identity betweenthe isoforms is ~50-80%, with the TM domains being well conserved. Both
extracellular loops contain characteristically conserved cysteine residues,which likely form intramolecular disulphide bonds. By contrast, the single
putative intracellular loop (between TM domains 2 and 3) and the cytoplasmicC terminus are highly variable among the family members.
Six connexins arethought to associate to form a hemi-channel, or connexon. Two connexons then
interact (likely via the extracellular loops of their connexins) to form thecomplete gap junction channel.
NH2-*** *** *************-COOH** ** ** **
** ** ** ** Cytoplasmic---**----**-----**----**----------------
** ** ** ** Membrane** ** ** **
---**----**-----**----**----------------** ** ** ** Extracellular
** ** ** **** **
Two sets of nomenclature have been used to identify the connexins. The
first, and most commonly used, classifies the connexin molecules accordingto molecular weight, such as connexin43 (abbreviated to Cx43), indicating
a connexin of molecular weight close to 43kDa. However, studies haverevealed cases where clear functional homologues exist across species
that have quite different molecular masses; therefore, an alternativenomenclature was proposed based on evolutionary considerations, which
divides the family into two major subclasses, alpha and beta, each with anumber of members [
]. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner []. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease []. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.Connexin36 (Cx36), which was recently cloned from mammalian brain, encodes
a protein containing 321 amino acid residues and predicted molecular massof ~36kDa [
]. The rat and mouse forms of Cx36 are near-identical,differing by only a single residue. Studies of its distribution (by mRNA
analysis), have found that is is highly expressed in the adult retina ofthese species, and also (less-abundantly) in the brain. Within the latter,
the highest expression levels are found in several discrete regions,including: the inferior olive, olfactory bulb, the CA3/CA4 sub-fields of
the hippocampus, and several of the brainstem nuclei.
Gap junction alpha-3 protein (also called connexin46, or Cx46) is a connexin
of ~415 amino acid residues. The bovine form is slightly shorter (401residues) and is hence known as Cx44, having a molecular mass of ~44 kD.
Cx46 (together with Cx50) is a connexin isoform expressed in the lens fibresof the eye. Here, gap junctions join the cells into a functional syncytium,
and also couple the fibres to the epithelial cells on the anterior surfaceof the lens. The lens fibres depend on this epithelium for their metabolic
support, since they lose their intra-cellular organelles, and accumulatehigh concentrations of crystallins, in order to produce their optical
transparency. Genetically-engineered mice deficient in Cx46 demonstrate theimportance of Cx46 in forming lens fibre gap junctions; these mice develop
normal lenses, but subsequently develop early onset senile-type cataractsthat resemble human nuclear cataracts. Aberrant proteolysis of crystallin proteins was observed in the lenses of Cx46-null mice [
]. A Cx46 mutant in a highly conserved threonine has been linked toautosomal dominant cataracts. This mutation causes loss of gap junction function and alters hemi-channel gating [
].
The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [
].Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca2+to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K
+concentration [
].The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [
,
].Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM
domains, with two extracellular and three cytoplasmic regions. This modelhas been validated for several of the family members by
in vitrobiochemical
analysis. Both N- and C-termini are thought to face the cytoplasm, and thethird TM domain has an amphipathic character, suggesting that it contributes
to the lining of the formed-channel. Amino acid sequence identity betweenthe isoforms is ~50-80%, with the TM domains being well conserved. Both
extracellular loops contain characteristically conserved cysteine residues,which likely form intramolecular disulphide bonds. By contrast, the single
putative intracellular loop (between TM domains 2 and 3) and the cytoplasmicC terminus are highly variable among the family members.
Six connexins arethought to associate to form a hemi-channel, or connexon. Two connexons then
interact (likely via the extracellular loops of their connexins) to form thecomplete gap junction channel.
NH2-*** *** *************-COOH** ** ** **
** ** ** ** Cytoplasmic---**----**-----**----**----------------
** ** ** ** Membrane** ** ** **
---**----**-----**----**----------------** ** ** ** Extracellular
** ** ** **** **
Two sets of nomenclature have been used to identify the connexins. The
first, and most commonly used, classifies the connexin molecules accordingto molecular weight, such as connexin43 (abbreviated to Cx43), indicating
a connexin of molecular weight close to 43kDa. However, studies haverevealed cases where clear functional homologues exist across species
that have quite different molecular masses; therefore, an alternativenomenclature was proposed based on evolutionary considerations, which
divides the family into two major subclasses, alpha and beta, each with anumber of members [
]. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner []. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease []. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.Gap junction alpha-1 protein (also called connexin43, or Cx43) is a connexin
of 381 amino acid residues (human isoform) that is widely expressed inseveral organs and cell types, and is the principal gap junction protein of
the heart. Characterisation of genetically-engineered mice that lack Cx43,and also of human patients that have spontaneously-occurring mutations in
the gene encoding it (GJA1), suggest Cx43 is essential for the developmentof normal cardiac architecture and ventricular conduction. Mice lacking Cx43
survive to term but die shortly after birth. They have cardiac malformationsthat lead to the obstruction of the pulmonary artery, leading to neonatal
cyanosis, and subsequent death. This phenotype is reminiscent of some formsof stenosis of the pulmonary artery. Human subjects with visceroatrial
heterotaxia (a heart disorder characterised by arterial defects), have beenfound to have points mutations in the Cx43-encoding gene, as a result of
which a potential phosphorylation site within the C terminus is disrupted. Consequently, although these mutant Cx43 molecules still form functional gap
junction channels, their response to protein kinase activation is impaired.
The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [
].Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca
2+to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K
+concentration [
].The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [
,
].Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM
domains, with two extracellular and three cytoplasmic regions. This modelhas been validated for several of the family members by
in vitrobiochemical
analysis. Both N- and C-termini are thought to face the cytoplasm, and thethird TM domain has an amphipathic character, suggesting that it contributes
to the lining of the formed-channel. Amino acid sequence identity betweenthe isoforms is ~50-80%, with the TM domains being well conserved. Both
extracellular loops contain characteristically conserved cysteine residues,which likely form intramolecular disulphide bonds. By contrast, the single
putative intracellular loop (between TM domains 2 and 3) and the cytoplasmicC terminus are highly variable among the family members.
Six connexins arethought to associate to form a hemi-channel, or connexon. Two connexons then
interact (likely via the extracellular loops of their connexins) to form thecomplete gap junction channel.
NH2-*** *** *************-COOH** ** ** **
** ** ** ** Cytoplasmic---**----**-----**----**----------------
** ** ** ** Membrane** ** ** **
---**----**-----**----**----------------** ** ** ** Extracellular
** ** ** **** **
Two sets of nomenclature have been used to identify the connexins. The
first, and most commonly used, classifies the connexin molecules according
to molecular weight, such as connexin43 (abbreviated to Cx43), indicatinga connexin of molecular weight close to 43kDa. However, studies have
revealed cases where clear functional homologues exist across speciesthat have quite different molecular masses; therefore, an alternative
nomenclature was proposed based on evolutionary considerations, whichdivides the family into two major subclasses, alpha and beta, each with a
number of members []. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner []. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease []. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.Gap junction beta-2 protein (also called connexin26, or Cx26) is a connexin
of 226 amino acid residues that is often found together with Cx32 inepithelial tissues. In rodents, it seems essential for normal embryonic
development; mice lacking Cx26 die in utero at about embryonic day 11.Absence of Cx26 impairs transplacental movement of glucose, thus impairing
embryonic development. In humans, spontaneously-occurring mutations in thegene encoding Cx26 have been found to be associated with a quite different
disorder, non-syndromic neurosensory autosomal recessive deafness, the mostcommon form of inherited hearing loss. Consistent with a role in auditory
transduction, Cx26 is the predominant connexin isoform expressed in theorgan of Corti of the cochlea. Here, it may be involved in maintaining the
ionic balance of the endolymph, by providing a pathway for ions necessaryto maintain this potassium-rich fluid.
Faithful inheritance of organelles by daughter cells is essential to retain the benefits afforded to eukaryotic cells by compartmentalisation of biochemical functions. In Saccharomyces cerevisiae, the class V myosin, Myo2p, is involved in transporting different organelles, including the peroxisome, along actin cables to the bud [
].Inp2p has been identified as the peroxisome-specific receptor for Myo2p. Cells lacking Inp2p fail to partition peroxisomes to the bud, although they are unaffected in the inheritance of other organelles. Inp2p is a peroxisomal membrane protein, interacting directly with the globular tail of Myo2p. Cells that over-produce Inp2p often transfer their entire populations of peroxisomes to buds. Levels of Inp2p oscillate with the cell cycle. Organelle-specific receptors like Inp2p illustrate how a single motor can move different organelles in distinct and specific patterns. Inp2p is the first peroxisomal protein implicated in the vectorial movement of peroxisomes [].
The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [
].Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca
2+to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K
+concentration [
].The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [
,
].Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM
domains, with two extracellular and three cytoplasmic regions. This modelhas been validated for several of the family members by
in vitrobiochemical
analysis. Both N- and C-termini are thought to face the cytoplasm, and thethird TM domain has an amphipathic character, suggesting that it contributes
to the lining of the formed-channel. Amino acid sequence identity betweenthe isoforms is ~50-80%, with the TM domains being well conserved. Both
extracellular loops contain characteristically conserved cysteine residues,which likely form intramolecular disulphide bonds. By contrast, the single
putative intracellular loop (between TM domains 2 and 3) and the cytoplasmicC terminus are highly variable among the family members.
Six connexins arethought to associate to form a hemi-channel, or connexon. Two connexons then
interact (likely via the extracellular loops of their connexins) to form thecomplete gap junction channel.
NH2-*** *** *************-COOH** ** ** **
** ** ** ** Cytoplasmic---**----**-----**----**----------------
** ** ** ** Membrane** ** ** **
---**----**-----**----**----------------** ** ** ** Extracellular
** ** ** **** **
Two sets of nomenclature have been used to identify the connexins. The
first, and most commonly used, classifies the connexin molecules accordingto molecular weight, such as connexin43 (abbreviated to Cx43), indicating
a connexin of molecular weight close to 43kDa. However, studies haverevealed cases where clear functional homologues exist across species
that have quite different molecular masses; therefore, an alternativenomenclature was proposed based on evolutionary considerations, which
divides the family into two major subclasses, alpha and beta, each with anumber of members [
]. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner []. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease []. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.Gap junction beta-1 protein (also called connexin32, or Cx32) is a connexin
of 283 amino acid residues (human isoform) that is widely expressed in manytissues, including the liver, exocrine pancreas, central nervous system and
epithelium of the gastrointestinal tract. The amphibian isoform from theXenopus laevis (African clawed frog), is slightly shorter, containing 264
amino acid residues. In the adult frog, the protein is present in the lungs,alimentary tract and ovaries [
].In humans, Cx32 appears to be critical to the functioning of Schwann cells,
which are responsible for the myelination of nerves in the peripheralnervous system. Mutations in the gene encoding Cx32 give rise to a form of
inherited neuropathy called X-linked Charcot-Marie-Tooth disease, whichaffects nervous conduction in both motor and sensory axons. To date, >40
different mutations have been identified, and these are spread throughoutmost of the Cx32 molecule. The effects of some of these mutations have been
determined, and several of them lead to a complete loss of gap junctionfunction. Targeted-gene disruption of Cx32 in mice has confirmed its role
in Schwann cell function; such Cx32-null mice also develop a form ofperipheral neuropathy similar to Charcot-Marie-Tooth disease.
The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [
].Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca2+to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K
+concentration [
].The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [
,
].Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM
domains, with two extracellular and three cytoplasmic regions. This modelhas been validated for several of the family members by
in vitrobiochemical
analysis. Both N- and C-termini are thought to face the cytoplasm, and thethird TM domain has an amphipathic character, suggesting that it contributes
to the lining of the formed-channel. Amino acid sequence identity betweenthe isoforms is ~50-80%, with the TM domains being well conserved. Both
extracellular loops contain characteristically conserved cysteine residues,which likely form intramolecular disulphide bonds. By contrast, the single
putative intracellular loop (between TM domains 2 and 3) and the cytoplasmicC terminus are highly variable among the family members.
Six connexins arethought to associate to form a hemi-channel, or connexon. Two connexons then
interact (likely via the extracellular loops of their connexins) to form thecomplete gap junction channel.
NH2-*** *** *************-COOH** ** ** **
** ** ** ** Cytoplasmic---**----**-----**----**----------------
** ** ** ** Membrane** ** ** **
---**----**-----**----**----------------** ** ** ** Extracellular
** ** ** **** **
Two sets of nomenclature have been used to identify the connexins. The
first, and most commonly used, classifies the connexin molecules accordingto molecular weight, such as connexin43 (abbreviated to Cx43), indicating
a connexin of molecular weight close to 43kDa. However, studies haverevealed cases where clear functional homologues exist across species
that have quite different molecular masses; therefore, an alternativenomenclature was proposed based on evolutionary considerations, which
divides the family into two major subclasses, alpha and beta, each with anumber of members [
]. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner []. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease []. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.Gap junction beta-3 protein (also called connexin31, or Cx31) is a connexin
of 270 amino acid residues, and belongs to a family that also includes Cx26,Cx31.1 and Cx32. At the mRNA level, it has been found to be expressed in the
skin, ear, placenta and eye. Mutations in Cx31 have been found to beresponsible for two quite different inherited human diseases: erythro-keratomdermia variablis and autosomal dominant hearing impairment. The
former is a hereditary skin disease characterised by transient figurate redpatches of skin and hyperkeratosis. In the Cx31 molecule of these patients,
either a conserved glycine has been substituted by a charged residue, or acysteine has been changed to a to serine residue [
]. In the latter,mutations in Cx31 result in high-frequency hearing impairment, making it
the second connexin molecule (together with Cx26) in which mutations havebeen found to be responsible for an inherited hearing disorder.
The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [
].Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca
2+to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K
+concentration [
].The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [
,
].Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM
domains, with two extracellular and three cytoplasmic regions. This modelhas been validated for several of the family members by
in vitrobiochemical
analysis. Both N- and C-termini are thought to face the cytoplasm, and thethird TM domain has an amphipathic character, suggesting that it contributes
to the lining of the formed-channel. Amino acid sequence identity betweenthe isoforms is ~50-80%, with the TM domains being well conserved. Both
extracellular loops contain characteristically conserved cysteine residues,which likely form intramolecular disulphide bonds. By contrast, the single
putative intracellular loop (between TM domains 2 and 3) and the cytoplasmicC terminus are highly variable among the family members.
Six connexins arethought to associate to form a hemi-channel, or connexon. Two connexons then
interact (likely via the extracellular loops of their connexins) to form thecomplete gap junction channel.
NH2-*** *** *************-COOH** ** ** **
** ** ** ** Cytoplasmic---**----**-----**----**----------------
** ** ** ** Membrane** ** ** **
---**----**-----**----**----------------** ** ** ** Extracellular
** ** ** **** **
Two sets of nomenclature have been used to identify the connexins. The
first, and most commonly used, classifies the connexin molecules accordingto molecular weight, such as connexin43 (abbreviated to Cx43), indicating
a connexin of molecular weight close to 43kDa. However, studies haverevealed cases where clear functional homologues exist across species
that have quite different molecular masses; therefore, an alternativenomenclature was proposed based on evolutionary considerations, which
divides the family into two major subclasses, alpha and beta, each with anumber of members [
]. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner []. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease []. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.Gap junction alpha-5 protein (also called connexin40, or Cx40) is a connexin
of ~357 amino acid residues. The chicken isoform is about ten residueslonger, and is hence known as connexin42 (Cx42), as it has a molecular mass
of ~42 kD. Targeted disruption of the gene encoding Cx40 in mice suggeststhat Cx40-containing gap junctions are involved in the rapid conduction of
impulses in the His-Purkinje system of the heart, which is responsible forthe coordinated spread of excitation from the atrioventricular (A-V) node
to the ventricular myocardium. Mice lacking Cx40 are viable and fertile;however, they have subtle electrocardio-graphic abnormalities, such as
partial A-V block. Studies of the distribution of Cx40 support thesefindings, since Cx40 has been reported to be prominently expressed in the
Purkinje fibres of the heart.
The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [].Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca
2+to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K
+concentration [
].The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [
,
].Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM
domains, with two extracellular and three cytoplasmic regions. This modelhas been validated for several of the family members by
in vitrobiochemical
analysis. Both N- and C-termini are thought to face the cytoplasm, and thethird TM domain has an amphipathic character, suggesting that it contributes
to the lining of the formed-channel. Amino acid sequence identity betweenthe isoforms is ~50-80%, with the TM domains being well conserved. Both
extracellular loops contain characteristically conserved cysteine residues,which likely form intramolecular disulphide bonds. By contrast, the single
putative intracellular loop (between TM domains 2 and 3) and the cytoplasmicC terminus are highly variable among the family members.
Six connexins arethought to associate to form a hemi-channel, or connexon. Two connexons then
interact (likely via the extracellular loops of their connexins) to form thecomplete gap junction channel.
NH2-*** *** *************-COOH** ** ** **
** ** ** ** Cytoplasmic---**----**-----**----**----------------
** ** ** ** Membrane** ** ** **
---**----**-----**----**----------------** ** ** ** Extracellular
** ** ** **** **
Two sets of nomenclature have been used to identify the connexins. The
first, and most commonly used, classifies the connexin molecules accordingto molecular weight, such as connexin43 (abbreviated to Cx43), indicating
a connexin of molecular weight close to 43kDa. However, studies haverevealed cases where clear functional homologues exist across species
that have quite different molecular masses; therefore, an alternativenomenclature was proposed based on evolutionary considerations, which
divides the family into two major subclasses, alpha and beta, each with anumber of members [
]. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner []. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease []. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.Gap junction alpha-4 protein (also called connexin37, or Cx37) is a connexin
of 333 amino acids (human isoform) with a predicted molecular mass of ~37kD. It is expressed in many organs and tissues, including: brain, heart,
uterus, ovary, and endothelial cells of blood vessels. When heterologouslyexpressed, Cx37 forms intercellular channels that are more sensitive to
voltage and show faster voltage-gating kinetics than most other previously-characterised gap junction channels. The recent generation of mice lackingthe gene encoding Cx37 (GJA4 or CXN-37) has shed some light on its function
in vivo. Female mice lacking Cx37 are viable and apparently in good health,
but are rendered infertile, as a result of a failure to ovulate. It appearsthat in the ovarian follicle, functional gap junctions (formed by Cx37) are
critical for communication between the oocyte and the surrounding granulosacells. Without Cx37, follicular development is arrested, and subsequently
ovulation does not occur.
The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [
].Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca
2+to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K
+concentration [
].The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [,
].Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM
domains, with two extracellular and three cytoplasmic regions. This modelhas been validated for several of the family members by
in vitrobiochemical
analysis. Both N- and C-termini are thought to face the cytoplasm, and thethird TM domain has an amphipathic character, suggesting that it contributes
to the lining of the formed-channel. Amino acid sequence identity betweenthe isoforms is ~50-80%, with the TM domains being well conserved. Both
extracellular loops contain characteristically conserved cysteine residues,which likely form intramolecular disulphide bonds. By contrast, the single
putative intracellular loop (between TM domains 2 and 3) and the cytoplasmicC terminus are highly variable among the family members.
Six connexins arethought to associate to form a hemi-channel, or connexon. Two connexons then
interact (likely via the extracellular loops of their connexins) to form thecomplete gap junction channel.
NH2-*** *** *************-COOH** ** ** **
** ** ** ** Cytoplasmic---**----**-----**----**----------------
** ** ** ** Membrane** ** ** **
---**----**-----**----**----------------** ** ** ** Extracellular
** ** ** **** **
Two sets of nomenclature have been used to identify the connexins. The
first, and most commonly used, classifies the connexin molecules accordingto molecular weight, such as connexin43 (abbreviated to Cx43), indicating
a connexin of molecular weight close to 43kDa. However, studies haverevealed cases where clear functional homologues exist across species
that have quite different molecular masses; therefore, an alternativenomenclature was proposed based on evolutionary considerations, which
divides the family into two major subclasses, alpha and beta, each with anumber of members [
]. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner []. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease []. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.Gap junction alpha-8 protein (also called connexin50, Cx50, or lens fibre
protein MP70) is a connexin of ~431 amino acid residues. The chicken isoformis shorter (399 residues) and is hence known as Cx45.6. Cx50 and Cx46 are
the two gap junction proteins normally found in lens fibre cells of the eye.Evidence from both genetically-engineered mice, and from the identification
of mutations in the human Cx50-encoding gene, highlight the importance ofthis connexin in maintaining lens transparency. Deletion of mice Cx50
produces a viable phenotype, but these animals start to develop cataracts(of the zonular pulverant type) at about one week old. They also have
abnormally small eyes and lenses. Similarly, mutations in the human geneencoding Cx50 have been associated with the occurrence of congenital
cataracts. Affected individuals develop cataracts (with zonular pulverentopacities), and analysis shows they have a single point mutation in the Cx50
coding region, resulting in a non-conservative substitution in the secondputative TM domain of a serine residue for a proline.
The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [
].Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca
2+to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K
+concentration [
].The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [
,
].Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM
domains, with two extracellular and three cytoplasmic regions. This modelhas been validated for several of the family members by
in vitrobiochemical
analysis. Both N- and C-termini are thought to face the cytoplasm, and thethird TM domain has an amphipathic character, suggesting that it contributes
to the lining of the formed-channel. Amino acid sequence identity betweenthe isoforms is ~50-80%, with the TM domains being well conserved. Both
extracellular loops contain characteristically conserved cysteine residues,which likely form intramolecular disulphide bonds. By contrast, the single
putative intracellular loop (between TM domains 2 and 3) and the cytoplasmicC terminus are highly variable among the family members.
Six connexins arethought to associate to form a hemi-channel, or connexon. Two connexons then
interact (likely via the extracellular loops of their connexins) to form thecomplete gap junction channel.
NH2-*** *** *************-COOH** ** ** **
** ** ** ** Cytoplasmic---**----**-----**----**----------------
** ** ** ** Membrane** ** ** **
---**----**-----**----**----------------** ** ** ** Extracellular
** ** ** **** **
Two sets of nomenclature have been used to identify the connexins. The
first, and most commonly used, classifies the connexin molecules accordingto molecular weight, such as connexin43 (abbreviated to Cx43), indicating
a connexin of molecular weight close to 43kDa. However, studies have
revealed cases where clear functional homologues exist across speciesthat have quite different molecular masses; therefore, an alternative
nomenclature was proposed based on evolutionary considerations, whichdivides the family into two major subclasses, alpha and beta, each with a
number of members []. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner []. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease []. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.Gap junction alpha-6 protein (also called connexin45, or Cx45) is a connexin
of 396 amino acid residues. It is one of four isoforms expressed in theheart (together with Cx43, Cx40 and Cx37). All four isoforms show differing
distribution patterns within the human heart: Cx45 tends to be detectableonly at rather low levels, with a trend toward higher levels in the atria
than the ventricles. Cx45 is also thought to be involved in the formation ofgap junctions between the bone-forming cells, osteoblasts; the extent of
their cell-cell coupling may act to modulate their gene expression.
This entry represents SpoVB, which is the stage V sporulation protein B of the bacterial endospore formation program in Bacillus subtilis and various other Firmcutes [
]. It is nearly universal among endospore-formers. Paralogs with high sequence similarity to SpoVB exist, such as YkvU from B. subtilis and a number Clostridium proteins, but they are excluded from this entry.
This family represents the stage III sporulation protein AF (SpoIIIAF) of the bacterial endospore formation program, which exists in some but not all members of the Firmicutes (formerly called low-GC Gram-positives). The C-terminal region of these proteins is poorly conserved.
The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [
].Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca
2+to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K
+concentration [
].The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [
,
].Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM
domains, with two extracellular and three cytoplasmic regions. This modelhas been validated for several of the family members by
in vitrobiochemical
analysis. Both N- and C-termini are thought to face the cytoplasm, and thethird TM domain has an amphipathic character, suggesting that it contributes
to the lining of the formed-channel. Amino acid sequence identity betweenthe isoforms is ~50-80%, with the TM domains being well conserved. Both
extracellular loops contain characteristically conserved cysteine residues,which likely form intramolecular disulphide bonds. By contrast, the single
putative intracellular loop (between TM domains 2 and 3) and the cytoplasmicC terminus are highly variable among the family members.
Six connexins arethought to associate to form a hemi-channel, or connexon. Two connexons then
interact (likely via the extracellular loops of their connexins) to form thecomplete gap junction channel.
NH2-*** *** *************-COOH
** ** ** **** ** ** ** Cytoplasmic
---**----**-----**----**----------------** ** ** ** Membrane
** ** ** **---**----**-----**----**----------------
** ** ** ** Extracellular** ** ** **
** **Two sets of nomenclature have been used to identify the connexins. The
first, and most commonly used, classifies the connexin molecules accordingto molecular weight, such as connexin43 (abbreviated to Cx43), indicating
a connexin of molecular weight close to 43kDa. However, studies haverevealed cases where clear functional homologues exist across species
that have quite different molecular masses; therefore, an alternativenomenclature was proposed based on evolutionary considerations, which
divides the family into two major subclasses, alpha and beta, each with anumber of members [
]. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner []. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease []. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.Gap junction beta-5 protein (also called connexin 31.1, or Cx31.1) is a
connexin of 271 amino acid residues that shares ~70% amino acid identitywith both Cx30.3 and Cx31 [
,
]. It is most closely related to the former;together these molecules share a rather restricted expression pattern,
being preferentially expressed in the skin, and undetectable in most othertissues. Additionally, the genes encoding them have been found to be
rather closely-linked on mouse chromosome 4 [].
The connexins are a family of integral membrane proteins that oligomerise to form intercellular channels that are clustered at gap junctions. These channels are specialised sites of cell-cell contact that allow the passage of ions, intracellular metabolites and messenger molecules (with molecular weight less than 1-2kDa) from the cytoplasm of one cell to its opposing neighbours. They are found in almost all vertebrate cell types, and somewhat similar proteins have been cloned from plant species. Invertebrates utilise a different family of molecules, innexins, that share a similar predicted secondary structure to the vertebrate connexins, but have no sequence identity to them [
].Vertebrate gap junction channels are thought to participate in diverse biological functions. For instance, in the heart they permit the rapid cell-cell transfer of action potentials, ensuring coordinated contraction of the cardiomyocytes. They are also responsible for neurotransmission at specialised 'electrical' synapses. In non-excitable tissues, such as the liver, they may allow metabolic cooperation between cells. In the brain, glial cells are extensively-coupled by gap junctions; this allows waves of intracellular Ca
2+to propagate through nervous tissue, and may contribute to their ability to spatially-buffer local changes in extracellular K
+concentration [
].The connexin protein family is encoded by at least 13 genes in rodents, with many homologues cloned from other species. They show overlapping tissue expression patterns, most tissues expressing more than one connexin type. Their conductances, permeability to different molecules, phosphorylation and voltage-dependence of their gating, have been found to vary. Possible communication diversity is increased further by the fact that gap junctions may be formed by the association of different connexin isoforms from apposing cells. However, in vitro studies have shown that not all possible combinations of connexins produce active channels [
,
].Hydropathy analysis predicts that all cloned connexins share a common transmembrane (TM) topology. Each connexin is thought to contain 4 TM
domains, with two extracellular and three cytoplasmic regions. This modelhas been validated for several of the family members by
in vitrobiochemical
analysis. Both N- and C-termini are thought to face the cytoplasm, and thethird TM domain has an amphipathic character, suggesting that it contributes
to the lining of the formed-channel. Amino acid sequence identity betweenthe isoforms is ~50-80%, with the TM domains being well conserved. Both
extracellular loops contain characteristically conserved cysteine residues,which likely form intramolecular disulphide bonds. By contrast, the single
putative intracellular loop (between TM domains 2 and 3) and the cytoplasmicC terminus are highly variable among the family members.
Six connexins arethought to associate to form a hemi-channel, or connexon. Two connexons then
interact (likely via the extracellular loops of their connexins) to form thecomplete gap junction channel.
NH2-*** *** *************-COOH** ** ** **
** ** ** ** Cytoplasmic---**----**-----**----**----------------
** ** ** ** Membrane** ** ** **
---**----**-----**----**----------------** ** ** ** Extracellular
** ** ** **** **
Two sets of nomenclature have been used to identify the connexins. The
first, and most commonly used, classifies the connexin molecules accordingto molecular weight, such as connexin43 (abbreviated to Cx43), indicating
a connexin of molecular weight close to 43kDa. However, studies haverevealed cases where clear functional homologues exist across species
that have quite different molecular masses; therefore, an alternativenomenclature was proposed based on evolutionary considerations, which
divides the family into two major subclasses, alpha and beta, each with anumber of members [
]. Due to their ubiquity and overlapping tissue distributions, it has proved difficult to elucidate the functions of individual connexin isoforms. To circumvent this problem, particular connexin-encoding genes have been subjected to targeted-disruption in mice, and the phenotype of the resulting animals investigated. Around half the connexin isoforms have been investigated in this manner []. Further insight into the functional roles of connexins has come from the discovery that a number of human diseases are caused by mutations in connexin genes. For instance, mutations in Cx32 give rise to a form of inherited peripheral neuropathy called X-linked dominant Charcot-Marie-Tooth disease []. Similarly, mutations in Cx26 are responsible for both autosomal recessive and dominant forms of nonsyndromic deafness, a disorder characterised by hearing loss, with no apparent effects on other organ systems.Gap junction beta-4 protein (also called connexin30.3, or Cx30.3) is a structural component of gap junctions. It is closely related to Cx31.1, being ~70% identical. Together, these connexin molecules show a very restricted expression pattern, being preferentially expressed in the skin [
]. This protein was also found in the cochlea, being associated with normal auditory function [].
This superfamily contains the bacterial Sigma factor-binding protein Crl. This is a transcriptional regulator of the csgA curlin subunit gene for curli fibres that are found on the surface of certain bacteria [
]. These proteins bind to the sigma-S subunit of RNA polymerase, activating expression of sigma-S-regulated genes. They also stimulate RNA polymerase holoenzyme formation and may bind to several other sigma factors, such as sigma-70 and sigma-32.
Centriolar and ciliogenesis-associated protein HYLS1
Type:
Family
Description:
Hydrolethalus syndrome (HLS) is an autosomal recessive lethal malformation syndrome, leading to still-birth, or death shortly after birth. The syndrome is characterised by hydrocephaly, with absent upper midline structures of the brain, micrognathia and polydactyly. A variety of other features (including cleft lip or palate, club feet, anomalies of the ears, eyes and nose, a keyhole-shaped defect in the occipital bone, abnormal genitalia, and congenital heart and respiratory organ defects) have also been observed in affected individuals [
]. Characterisation of the underlying molecular defect is important, as it could both expose new molecular pathway(s) essential for normal human development and provide new insights into foetal malformation syndromes.The critical HLS region has been defined to a 476 kb interval using cases from 30 Finnish HLS families [
]. Within this region, sequence analysis has revealed a point mutation in a novel gene (termed HYLS1) that results in substitution of a well-conserved Asp by Gly in the Centriolar and ciliogenesis-associated protein HYLS1, which is essential for early development of the human foetus [].HYLS1 is dispensable for centriole assembly and centrosome function in cell division. Instead, HYLS1 plays an essential role in cilia formation that is conserved between C. elegans and vertebrates [
].
This entry represents SpoVID, the stage VI sporulation protein D, which is restricted to endospore-forming bacteria, all of which are found among the Firmicutes. It is widely distributed but not quite universal in this group. Between well-conserved N-terminal and C-terminal domains is a poorly conserved, low-complexity region of variable length, rich in glutamic acid. SpoVID is involved in spore coat assembly in the mother cell compartment late in the process of sporulation.
Members of this entry include YlbJ, from Bacillus subtilis. They are found exclusively in the Firmicutes (low-GC Gram-positive bacteria) and are known from studies in B. subtilis to be part of the sigma-E regulon [
]. Mutation leads to a sporulation defect, confirming that members of this entry are involved in sporulation. The protein appears to be universal among endospore-forming bacteria, and in Symbiobacterium thermophilum IAM 14863, there are two ORFs encoding YlbJ that are distant from each other.
This entry contains the stage II sporulation protein E (SpoIIE,
), which is a multiple membrane spanning protein with two separable functions. It plays a role in the switch to polar cell division during sporulation and it has phosphatase activity, located in the C-terminal region, which is required to activate sigma-F by dephosphorylating the phosphoprotein SpoIIAA-P [
]. All members of this entry are found in endospore-forming Gram-positive bacteria. A homologous protein, not a member of this entry, is found in the Cyanobacterium-like (and presumably non-spore-forming) photosynthesizer Heliobacillus mobilis.
The extracellular matrix component hyaluronan plays important roles in various processes of organogenesis, cell migration and cancer []. Recognition of and binding to hyaluronan is mediated by cell surface receptors.The proteins in this family were initially called receptor for hyaluronan mediated motility (RHAMM), and were thought to be involved in cell motility []. However, several lines of evidence suggest that they do not function as a conventional motility receptors for hyaluronan, leading to the suggestion they should be renamed intracellular hyaluronic acid binding protein (IHABP) [,
].IHABP is overexpressed in many cancers and may be involved in cellular transformation and metastasis formation [], and in regulating extracellular-regulated kinase (ERK) activity [].
Proteins in this entry include the stage V sporulation protein K (SpoVK), a close homologue of the Rubisco expression protein CbbX (
), and are members of an ATPase family associated with various cellular activities. These proteins are strictly limited to bacterial endospore-forming species, but are not found universally among members of this group; they are missing from the Clostridium species.
There is currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function. Members of this entry are mainly found in proteobacteria.
There is currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function. Members of this entry are mainly found in proteobacteria.
tRNA wybutosine-synthesizing protein 2 is an S-adenosyl-L-methionine-dependent transferase that acts as a component of the wybutosine biosynthesis pathway. It catalyses the transfer of the alpha-amino-alpha-carboxypropyl (acp) group from S-adenosyl-L-methionine to the C-7 position of 4-demethylwyosine (imG-14) to produce wybutosine-86 [
,
]. Wybutosine is a hyper modified guanosine with a tricyclic base found at the 3'-position adjacent to the anticodon of eukaryotic phenylalanine tRNA.
Nitrogenase, also called dinitrogenase, is the enzyme which catalyses the conversion of molecular nitrogen to ammonia (biological nitrogen fixation) [
,
]. The most widespread and most efficient nitrogenase contains a molybdenum cofactor. This protein family, VnfK, represents the beta subunit of the vanadium-containing V nitrogenase. It is homologous to NifK and AnfK, of the molybdenum-containing and the iron-only types, respectively.
Proteins in this entry include Anf1 from Rhodobacter capsulatus (Rhodopseudomonas capsulata) and AnfO from Azotobacter vinelandii. They are found exclusively in species which contain the iron-only nitrogenase, and are encoded immediately downstream of the structural genes for the nitrogenase enzyme in these species.
LptC is involved in the translocation of lipopolysaccharide (LPS) from the inner membrane to the outer membrane in Gram-negative bacteria [
]. It facilitates the transfer of LPS from the inner membrane to a periplasmic chaperone, LptA [,
].
ArdA functions in bacterial conjugation to allow an unmodified plasmid to evade restriction in the recipient bacterium and yet acquire cognate modification [
]. ArdA forms a dimer and each monomer is comprised of three small α-β domains, each with a different fold, arranged in a row in each monomer.
This superfamily represents the bacterial antirestriction (ArdA) protein C-terminal domain 3. Structurally, this domain consists of three-stranded β-sheet and three α-helices packed together in a manner that creates a groove in the structure. The helical arrangement in the C-terminal domain contains a component of the winged helix-turn-helix motif. The evolution of ArdA is curious as domains 2 (
) and 3 (
) show a similar fold to that of nucleotide binding proteins but the opposite charge to the characteristic positive charge of oligonucleotide binding proteins. This reversal in surface potential suggests that ArdA is not a DNA- (or RNA)-binding protein [
].
ArdA functions in bacterial conjugation to allow an unmodified plasmid to evade restriction in the recipient bacterium and yet acquire cognate modification []. ArdA forms a dimer and each monomer is comprised of three small α-β domains, each with a different fold, arranged in a row in each monomer.This superfamily represents the antirestriction protein (ArdA) domain 2. Domains 2 and 3 (
) have folds similar to those of nucleotide binding proteins, but which present a negative potential, opposite to the positive potential characteristic of nucleotide binding proteins. This reversal in surface potential suggests that ArdA is not a DNA- (or RNA)-binding protein [
].
ArdA functions in bacterial conjugation to allow an unmodified plasmid to evade restriction in the recipient bacterium and yet acquire cognate modification [
]. ArdA forms a dimer and each monomer is comprised of three small α-β domains, each with a different fold, arranged in a row in each monomer.This superfamily represents the bacterial antirestriction (ArdA) protein N-terminal domain 1. Structurally, it consists of a three-stranded anti-parallel β-sheet and one short α-helix interspersed with three large loops of 10 or more residues. Domain 1 is not essential for anti-restriction as it can be deleted, indicating that the key aspect of anti-restriction by ArdA is the binding to the MTase core using domains 2 (
) and 3 (
) [
].
Inositol 1,4,5-trisphosphate receptor-interacting protein family
Type:
Family
Description:
The inositol 1,4,5-trisphosphate receptor (IP(3)R) is a large, endoplasmic reticulum (ER)-resident protein that is a key regulator of intracellular Ca(2+) signalling [
]. Inositol 1,4,5-trisphosphate is formed in response to the activation of G protein-coupled receptors or tyrosine kinase receptors located in the plasma membrane, which elicit IP(3)R-mediated Ca(2+) release from ER stores [].The IP(3)R contains an N-terminal IP(3) recognition site and a C-terminal Ca(2+)-channel domain; between them is a large interaction domain for regulatory proteins, including calmodulin, chromgranins, glyceraldehyde-3- phosphate dehydrogenase, RACK1 and caldendrin [
]. These proteins regulate IP(3)R in diverse ways, but only two regulators have been shown to influence Ca(2+) sensitivity [].A protein termed DANGER has been identified as a novel IP(3)R-interacting protein [
]. DANGER is membrane-associated and predicted to contain a partial MAB-21 domain. It is expressed in a wide variety of neuronal cell lineages, where it localises with IP(3)R to membranes in the cell periphery. DANGER interacts with IP(3)R in vitro and co-immuno- precipitates with IP(3)R from cellular preparations; it robustly enhances Ca(2+)-mediated inhibition of IP(3)R Ca(2+) release without affecting IP(3) binding in microsomal assays, and inhibits gating in single-channel recordings of IP(3)R. The protein appears to allosterically modulate the sensitivity of IP(3)R to Ca(2+) inhibition, which probably alters IP(3)R-mediated Ca(2+) dynamics in cells where DANGER and IP(3)R are co-expressed [].
Proteins in this family are components of the mitochondrial ribosome small subunit (28S) which comprises a 12S rRNA and about 30 distinct proteins [
]. This protein was previously identified as Imogen 38 (NP_065585) which is a 38kDa mitochondrial autoantigen associated with type 1 diabetes []. Its relationship to the etiology of this disease remains to be clarified.
Submaxillary gland androgen-regulated protein like
Type:
Family
Description:
This entry includes submaxillary gland androgen-regulated proteins SMR1,SMR2, SMR3. This entry also includes opiorphin prepropeptide from humans. SMR1 gene gives rise to four related peptides: SMR1-undecapeptide, SMR1-hexapeptide, SMR1-pentapeptide [
] and submandibular gland peptide T [].Submandibular gland peptide T is able to down-regulate cardiovascular depression induced by septic or anaphylactic shock [
].SMR1-pentapeptide (also called Sialorphin) may be involved in the modulation of mineral balance between at least four systems: kidney, bone, tooth and circulation. It is synthesized predominantly in the submandibular gland and prostate of adult rats in response to androgen steroids and is released locally and systemically in response to stress. It is an endogenous inhibitor of neprilysin. It inhibits the breakdown of Met-enkephalin and substance P in isolated tissue from the dorsal zone of the rat spinal cord. It has an analgesic effect when administered to rats by intravenous injection [
,
,
].
Reovirus nonstructural protein sigma NS exhibits a ssRNA-binding activity and is thought to be involved in assembling the reovirus mRNAs for genome replication and virion morphogenesis. Various studies have been carried out to localize the RNA-binding site [
]. They suggest that the first 11 amino acids of sigma NS, which are predicted to form an amphipathic α-helix, are important for both ssRNA binding and formation of complexes larger than 7-9 S.A number of other studies have attempted to identify and characterise the RNA-binding activities of sigma NS. A study of the Avian orthoreovirus sigma NS protein suggests that it binds to single-stranded RNA in a nucleotide sequence non-specific manner and is functionally similar to its counterpart specified by mammalian reovirus [
].
Rotaviruses are dsRNA viruses that appear to infect a wide range of mammals. Gene 11 product is a non-structural phosphoprotein designated as NS26, now more commonly annotated as non-structural protein 5 (NSP5) [
].
This family consists of the histone stem-loop-binding protein (SLBP1) and the Xenopus Oocyte-specific histone RNA stem-loop-binding protein 2 (SLBP2). They both bind to the 3' end of histone mRNA in frog oocytes. However, their functions are different. SLBP1 participates in histone pre-mRNA processing in the nucleus, while oocyte specific SLBP2 doesn't support the histone pre-mRNA processing and locates in the cytoplasm [
]. SLBP1 binds the 5' side of the stem-loop structure of replication-dependent histone pre-mRNAs and contributes to efficient 3'-end processing by stabilising the complex between histone pre-mRNA and U7 small nuclear ribonucleoprotein (snRNP), via the histone downstream element (HDE) [
]. It plays an important role in targeting mature histone mRNA from the nucleus to the cytoplasm and to the translation machinery. It stabilises mature histone mRNA and could be involved in cell-cycle regulation of histone gene expression [,
,
,
]. SLBP2 binds to translationally inactive histone mRNA stored in immature oocytes. When oocytes mature, SLBP2 is degraded and a larger fraction of the histone mRNA is bound to SLBP1. Instead of having a role in histone pre-mRNA processing, SLBP2 may be a specific translational repressor [
].
MNS1 is a skeletal protein involved in organisation of the nuclear or perinuclear architecture and may affect the nuclear morphology during meiotic prophase in spermatocytes [
,
].
The temperate bacteriophage P2 has four defined tail genes: V, J, W and I. Their order is the late gene promoter, VWJI, followed by the tail fibre genes H and G and then a transcription terminator. BAP V protein is the small spike at the tip of the tail and basal plate assembly protein J lies at the edge of the baseplate [
]. This group represents the predicted baseplate assembly protein J.
Escherichia coli DinF is a membrane protein that has been found to protect cells against oxidative stress and bile salts [
]. The expression of DinF is regulated as part of the SOS system. It may act by detoxifying oxidizing molecules that have the potential to damage DNA []. Some member of this family have been reported to enhance the virulence of plant pathogenic bacteria by enhancing their ability to grow in the presence of toxic compounds [].This entry also includes DETOXIFICATION 42-47 (DTX42-47) from Arabidopsis. DTX42 (also known as AtMATE) is a citrate transporter critical for aluminum tolerance [
]. DTX43 is a citrate transporter responsible for loading citrate into xylem tissues, which helps facilitate iron transport to shoots [,
].In general, proteins from the MATE family are involved in exporting metabolites across the cell membrane and are often responsible for multidrug resistance (MDR) [
,
]. These proteins mediate resistance to a wide range of cationic dyes, fluroquinolones, aminoglycosides and other structurally diverse antibodies and drugs. MATE proteins are found in bacteria, archaea and eukaryotes. These proteins are predicted to have 12 α-helical transmembrane regions, some of the animal proteins may have an additional C-terminal helix [].
Uncharacterised conserved protein UCP019307, cupin-type
Type:
Family
Description:
This group contains proteins with the conserved barrel domain of the cupin superfamily (cupin fold) [
,
,
,
]. There are currently no experimental data for members of this group.
There is currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function. However, they are predicted to be integral membrane proteins (with several transmembrane segments).
Uncharacterised conserved protein UCP031503, transmembrane
Type:
Family
Description:
There is currently no experimental data for members of this group of predicted transmembrane proteins or their homologues, nor do they exhibit features indicative of any function.
Uncharacterised conserved protein UCP033093, metallophosphoesterase-type
Type:
Family
Description:
These conserved bacterial proteins contain one copy of the calcineurin-like phosphoesterase domain (
) and possess most of the motifs characteristic of a variety of enzymatically active phosphoesterases [
], including acid and alkaline phosphatases, phosphoprotein phosphatases, 5'-nucleotidase, bis(5'-nucleosyl)-tetraphosphatase (symmetrical), sphingomyelin phosphodiesterase, 2',3'-cylic-nucleotide 2'-phosphodiesterase, and 3',5'-nucleotide phosphodiesterase CpdA. Although this group appears to be similar to exonuclease SbcD (
), their catalytic activity, if any, is speculative.
There is currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function. Members of this entry are mainly found in proteobacteria.
This family consists of several hypothetical bacterial proteins, which seem to be found exclusively in Rhizobium and Ralstonia species. Members of this family are typically around 210 residues in length and contain 5 highly conserved cysteine residues at their N terminus. The function of this family is unknown.
Uncharacterised conserved protein UCP034961, SH3-2
Type:
Family
Description:
SH3 (src Homology-3) domains are small protein modules containing approximately 50 amino acid residues [
,
]. They are found in a great variety of intracellular or membrane-associated proteins [,
,
] for example, in a variety of proteins with enzymatic activity, in adaptor proteins, such as fodrin and yeast actin binding protein ABP-1.The SH3 domain has a characteristic fold which consists of five or six β-strands arranged as two tightly packed anti-parallel β-sheets. The linker regions may contain short helices. The surface of the SH3-domain bears a flat, hydrophobic ligand-binding pocket which consists of three shallow grooves defined by conservative aromatic residues in which the ligand adopts an extended left-handed helical arrangement. The ligand binds with low affinity but this may be enhanced by multiple interactions. The region bound by the SH3 domain is in all cases proline-rich and contains PXXP as a core-conserved binding motif. The function of the SH3 domain is not well understood but they may mediate many diverse processes such as increasing local concentration of proteins, altering their subcellular location and mediating the assembly of large multiprotein complexes [
].This group consists of prokaryotic proteins containing one to two SH3_2 domains, but there is currently no experimental data for these proteins.
Gp6, a Staphylococcus aureus pathogenicity island 1 protein, is a mobile genetic element that carries genes for several superantigen toxins. It is a dimeric protein produced from the pathogenicity island with a helix-loop-helix motif similar to that of bacteriophage scaffolding proteins. It is thought to determine the size of the capsids of distribution of the SAPI1 genome as it acts as an internal scaffolding protein during capsid size determination [
].
Uncharacterised conserved protein UCP007050, HI0931
Type:
Family
Description:
There is currently no experimental data for members of this group or their homologues, nor do they exhibit features indicative of any function. Members of this entry are mainly found in proteobacteria.
The first characterised methanobactin is made from a ribosomal precursor in Methylosinus trichosporium OB3b. Two additional species with homologous precursor peptides are Azospirillum sp. B510 and Gluconacetobacter sp. SXCC-1. This entry describes a clique of related sequences that occur always and only next to a methanobactin precursor [
].
Uncharacterised conserved protein UCP006425, beta-propeller-type
Type:
Family
Description:
There is currently no experimental data characterising members of this group or their homologues. However, they contain a β-propeller domain distantly related to WD-40 repeats in their mid- to C-terminal part (SCOP superfamily WD40 as detected by SMART with marginal score). Members of this group are thought to be secreted proteins based on the predicted signal peptide. Members are from prokaryotes.
Uncharacterised protein family, phage P2-GpU-fusion
Type:
Family
Description:
This entry consists of bacterial aproteins, restricted to Pseudomonas and Burkholderia species, of around 250 to 290 residues in length. The proteins all have a C-terminal bacteriophage P2 GpU domain, which is thought to be involved in tail assembly [
]. These proteins are probable fusion proteins of unknown function.
This entry contains proteins, which are functionally uncharacterised. Some members of this family appear to be miss-annotated as RocC an amino acid transporter from Bacillus subtilis.
Uncharacterised conserved protein UCP016662, toprim-type
Type:
Family
Description:
Members of this group contain the Toprim domain (topoisomerase-primase)
common to DnaG primases, type IA and type II topoisomerases, OLD family nucleases, as well as small primase-like proteins from bacteria and archaea, and bacterial DNA repair proteins of the RecR/M family [
].The domain consists of approximately 100 amino acids and have two conserved motifs, one of which centres at a conserved glutamate and the other one at two conserved aspartates (DxD). Examination of the structure of Topo IA and Topo II and modelling of the Toprim domains of the primases reveal a compact beta/alpha fold, with the conserved negatively charged residues juxtaposed, and inserts seen in Topo IA and Topo II [
]. The conserved glutamate may act as a general base in nucleotide polymerisation by primases and in strand rejoining by topoisomerases and as a general acid in strand cleavage by topoisomerases and nucleases. The role of this glutamate in catalysis is supported by site-directed mutagenesis data on primases and Topo IA []. The DxD motif may coordinate Mg2+that is required for the activity of all Toprim-containing enzymes. The common ancestor could encode a prototype Toprim enzyme that might have had both nucleotidyl transferase and polynucleotide cleaving activity [
].There is currently no experimental data for members of this group. As they lack the additional domains that are involved in numerous interactions typical of the larger proteins of the Toprim superfamily (primases and topoisomerases), they may represent a novel class of nucleotidyl transferases or nucleases [
].
The initial member of this family to be characterised was described as a DNA-binding protein from starved cells-like (Dps-like) protein, from the hyperthermophilic acidophile Sulfolobus solfataricus [
]. The protein was shown to share high sequence similarity with hypothetical proteins in other archaeal and bacterial genomes, several of which form a monophyletic cluster within the broad superfamily of ferritin-like diiron-carboxylate proteins, which are non-haem iron storage proteins [].The S. solfataricus Dps-like protein has been shown to self-assemble into a hollow dodecameric protein cage having tetrahedral symmetry, which uses H2O2 to oxidize Fe(II) to Fe(III), storing the oxide as a mineral core on the interior surface of the protein cage. It may be involved in the mitigation of oxidative damage [].
