This family, UPF0299, is represented by YohJ, an inner membrane protein with four predicted transmembrane domains; the C terminus is located in the periplasm [
]. The proteins in this entry are functionally uncharacterised.
This family consists of several hypothetical bacterial proteins of around 90 residues in length. The function of this family is unknown; however they form α-helical bundles and are thought to be involved in control of cell shape [
].
The N-terminal domain of the FlgJ protein is directly involved in flagellar rod assembly, while the adjacent C-terminal domain is a flagellum-specific muramidase (peptidoglycan hydrolase) required for formation of the outer membrane L ring [
].
This entry represents a group of bacterial proteins that are membrane proteins that effect the expression of haemolysin under anaerobic conditions [
].
This entry represents the TusA family of sulfur carrier proteins. TusA (also known as SirA, UvrY and YhhP) belongs to a group of five proteins (TusA-E) which together are responsible for 2-thiouridylation of 5-methylaminomethyl-2-thiouridine at tRNA wobble positions. TusA accepts sulfur from cysteine desulfurase IscS and transfers it in turn to TusD [
].
Members of this small but broadly distibuted (Gram-positive, Gram-negative, and Archaeal) family appear to have multiple transmembrane segments. The function is unknown.
This entry represents a group of AAA ATPases, including Pch2 from eukaryotes. It is required for the meiotic checkpoint that prevents chromosome segregation when recombination and chromosome synapsis are defective [
]. In humans it is linked to Mosaic variegated aneuploidy syndrome 3 (MVA3) [].This entry also includes a group of uncharacterised AAA domain-containing proteins from bacteria, including Cap6 (also known as TRIP13) from Pseudomonas aeruginosa. Cap6 is a homologue of Pch2. It is part of the CBASS (cyclic oligonucleotide-based antiphage signaling system) and functions as an AAA+ ATPase that prevents the CdnD:Cap7:Cap8 complex from synthesizing 2',3',3'-cyclic AMP-AMP-AMP (cAAA), which is a second messenger [
]. Cap6 binds and disassembles the active CD-NTase:HORMA complex, and hence functions as a negative regulator of CBASS [].
This entry represents a group of CRC domain-containing proteins, including TSO1 and TCX2/3/4 from Arabidopsis. They are are homologues of the LIN54 DNA-binding components of the mammalian DREAM complex, a protein complex responsible for the regulation of cell cycle-dependent gene expression. TSO1 has been shown to regulate meristem organization and cell division [
,
]. It may transcriptionally represses MYB3R1 (a conserved cell cycle regulator), and together they coordinate cell proliferation with differentiation in shoot and root []. TCX3 (also known as SOL1) and TCX2 (also known as SOL2) have been shown to regulate fate transition and cell divisions in the Arabidopsis stomatal lineage [].
This entry represents a group of plant proteins, including NIP1/2 and NIPL1/2 from Arabidopsis. NIP1 and NIP2 are integral thylakoid membrane proteins that contain three N-terminal transmembrane helixes and a C-terminal RING domain. NIP1/2 interact with plastid phage-type RNA polymerase RPOTmp and fixes RPOTmp on the stromal side of the thylakoid membrane [
]. The function of NIPL1/2 is not clear.
In the cyanobacterium Synechococcus species PCC 7942 (
), nblA triggers degradation of light-harvesting phycobiliproteins in response to deprivation nutrients including nitrogen, phosphorus and sulphur. The mechanism of nblA function is not known, but it has been hypothesised that nblA may act by disrupting phycobilisome structure, activating a protease or tagging phycobiliproteins for proteolysis. Members of this family have also been identified in the chloroplasts of some red algae.
This entry represents a group of plant CRIB domain-containing proteins including RIC1-11 (exclude 2 and 4) from Arabidopsis. They belong to the RIC (ROP-interactive CRIB motif-containing protein) family. RIC1 is inactivated by active ROP2 in the lobe-forming regions of pavement cells, which suppresses MT assembly, but promotes fine F-actin assembly and thereby induces outgrowth of the region. In contrast, RIC1 is activated by active ROP6 in the neck-forming regions of pavement cells, and then promotes the assembly of MTs, which limits the expansion of the region and results in the formation of a narrow neck. RIC1 also positively regulates the auxin effect and negatively regulates the ABA effect during root growth and lateral root development [].RIC7 functions as downstream effector of active ROP2 which is involved in the prevention of excessive stomatal opening upon light stimulation [
]. It is also involved in pollen tube growth regulation through its interaction with ROP1 [].The RIC (ROP-interactive CRIB motif-containing protein) family members act as Rho GTPase (Rop) targets that function in distinct Rop signaling pathways [
]. RICs interact with multiple ROP GTPases via their conserved CRIB motif, and link ROP proteins to diverse target molecules that bind to their variable domains []. RICs share several consensus amino acid residues upstream of the CRIB motif and a consensus PSWMXDFK block downstream of the CRIB motif. Unlike other group members, members of group V, consisting of RIC4 and RIC2, lack the PSWMXDFK block and contain a relatively long N terminus in front of the CRIB motif and a short C terminus [].
This entry represents a group of plant CRIB domain-containing proteins including RIC2 and RIC4 from Arabidopsis. They belong to the RIC (ROP-interactive CRIB motif-containing protein) family. It has been shown that overexpression of RIC2 in tobacco germinating pollen reduces pollen tube elongation [
].ROP1 and ROP6 have been shown to interact with RIC4, which promotes F-actin assembly. Together, they are involved in various processes of F-actin dynamics, cell growth, and plant/microbe interactions [
].The RIC (ROP-interactive CRIB motif-containing protein) family members act as Rho GTPase (Rop) targets that function in distinct Rop signaling pathways [
]. RICs interact with multiple ROP GTPases via their conserved CRIB motif, and link ROP proteins to diverse target molecules that bind to their variable domains []. RICs share several consensus amino acid residues upstream of the CRIB motif and a consensus PSWMXDFK block downstream of the CRIB motif. Unlike other group members, members of group V, consisting of RIC4 and RIC2, lack the PSWMXDFK block and contain a relatively long N terminus in front of the CRIB motif and a short C terminus [].
The myelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the velocity of axonal impulse conduction. Myelin protein P0 (MYP0), is a major component of the myelin sheath in peripheral nerves [
]. It comprises a an immunoglobulin (Ig)-like extracellular domain, a single transmembrane helix, and a cytoplasmic extension in the C terminus. It is postulated that MYP0 is a structural element in the formation and stabilisation of peripheral nerve myelin, which mediates adhesion between adjacent myelin wraps and ultimately drives myelin compaction [,
,
,
,
]. MYP0 consists of an immunoglobulin (Ig)-like extracellular domain, a single transmembrane helix, and a cytoplasmic extension of about 69 amino acids is the C terminus. Several peripheral neuropathies have been related to MYP0 [
].This entry represents the extracellular domain found at the C-terminal end of MYPO in chordates. This domain of about 69 amino acids is the region that interacts with the protein p65 [
]. The crystal structure of this domain showed a v-type immunoglobulin fold consisting of nine antiparallel beta strands forming a barrel-like shape []. It is associated to the membrane of Schwann cells and contributes to its physical properties, although these interactions can be directly affected by ions [,
].
Pentatricopeptide repeat-containing protein BIR6-like
Type:
Family
Description:
This entry represents a group of pentatricopeptide repeat-containing proteins from plants, including BIR6 (also known as At3g48250) from Arabidopsis. BIR6 is a mitochondrial protein implicated in splicing of intron 1 of mitochondrial nad7 transcripts [
].
This entry represents a group of SNF2 domain-containing proteins from plants, including CLSY1-3 and DRD1 from Arabidopsis. CLSY and DRD1 contain a SNF2-like domain and a helicase domain near the C terminus. They are required for siRNA-directed DNA methylation in Arabidopsis
[,
]. Polymerases IVa/Pol IV and Pol IVb/Pol V are plant-specific RNA polymerases involved in in multiple small RNA-mediated gene silencing pathways. CLSY1 is required for proper localization of both NRPD1 (the largest subunit of Pol IV) and RDR2 []. DRD1 has been shown to mediate RNA polymerases IV and V (Pol IV and Pol V) recruitment to chromatin [,
]. Interestingly, DRD1 and Pol V appear to be required not only for RNA-directed de novo methylation, but also for full erasure of methylation when the RNA trigger is withdrawn [].
This entry represents a domain found in nuclear migration protein nudC, which is implicated in cell division through the regulation of cytoplasmic dynein [
,
]. NudC may play a role not only in mitosis and cytokinesis [], but also in interkinetic nuclear migration and neuronal migration during neocortical development [].
Universal stress protein B (UspB) in Escherichia coli is a 14kDa protein which is predicted to be an integral membrane protein. Over expression of UspB results in cell death in stationary phase, and mutants of UspB are sensitive to ethanol exposure during stationary phase [
].
This entry represents proteins spore coat proteins Z (aka CotZ) and Y (aka CotY). They belong to a cysteine-rich spore coat family and are necessary for the assembly of intact exosporium.
This family represents functionally uncharacterised proteins found in bacteria, including YhjQ from Bacillus subtilis. They form a 4-helical bundle with a bromodomain-like topology and contain highly conserved cysteines in a repeated pattern, whose side chains appear buried.
RUNKEL is a microtubule-associated kinase-like protein involved in both phragmoplast-based cytokinesis in somatic cells and syncytial cytokinesis in reproductive cells [
]. RUNKEL may not have kinase activity [].
This entry represents a group of putative plant calcium-binding proteins, including CML48/49/50 from Arabidopsis and CBP from rice. CBP functions in calcium-mediated signalling processes [
].
This entry represents a group of plant PX domain-containing proteins, including EREX and EREL1/2 from Arabidopsis. EREX interacts with ARA7 and RHA1 (RAB5 members), whereas EREL1/2 was not shown to interact with these RAB5 members. EREX serves as an effector of canonical RAB5 GTPases and regulates membrane trafficking to protein storage vacuole. EREX and EREL1 act in the same trafficking and developmental events, while EREL2 has a partially redundant function with EREX and EREL1 [
].
Intraflagellar transport of ciliary precursors such as tubulin from the cytoplasm to the ciliary tip is required for ciliogenesis [
]. Intraflagellar transport protein 74 (IFT74) is a component of the intraflagellar transport (IFT) complex B, which contains at least 20 different protein subunits. Together with IFT81, it forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium [].
Intraflagellar transport of ciliary precursors such as tubulin from the cytoplasm to the ciliary tip is required for ciliogenesis [
]. Intraflagellar transport protein 81 (IFT81) is a component of the intraflagellar transport (IFT) complex B, which contains at least 20 different protein subunits. Together with IFT74 forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium [].
Members of this family include FapA (flagellar assembly protein A),
, found in Vibrio vulnificus. The synthesis of flagella allows bacteria to respond to chemotaxis by facilitating motility. Studies examining the role of FapA show that the loss or delocalization of FapA results in a complete failure of the flagellar biosynthesis and motility in response to glucose mediated chemotaxis. The polar localization of FapA is required for flagellar synthesis, and dephosphorylated EIIAGlc (Glucose-permease IIA component) inhibited the polar localization of FapA through direct interaction [
].
FlgD is known to be absolutely required for hook assembly, yet it has not been detected in the mature flagellum [
]. It appears to act as a hook-capping protein to enable assembly of hook protein subunits [].
Mycobacterial species are usually slender, curved rods with a unique cell
wall of complex waxes and glycolipids. They are resistant to acids, alkalisand dehydration, and are very slow to grow
in vitro. The human
pathogenic Mycobacteria (Mycobacterium tuberculosis and Mycobacterium leprae) are becoming resistant to conventional treatments and, together with HIV-related diseases, are fast posing a global health threat. An essential requirement, particularly of M. tuberculosis, is to gain entrance to, and to resist, the hostile intra-cellular environment of epithelial cells [].The genome of M. tuberculosis contains four mammalian cell entry (mce) operons [
], which are widely distributed in both pathogenic and non-pathogenic mycobacteria suggesting that the presence of these putative virulence genes is not an indicator for the pathogenicity of the bacilli. At the 5' end of the transcriptional unit are two genes that have evolved from a tandem duplication, and whose products resemble YrbE, a conserved hypothetical protein found in Escherichia coli, Haemophilus influenzae and Porphyra purpurea. All of the YrbE proteins, including the eight from M. tuberculosis, are probable integral membrane proteins with six TM alpha helices. The next six genes in each operon, the mce genes, are related, their products ranging in size from 275 to 564 amino acid residues. The corresponding protein sequences contain a number of highly conserved motifs that define a 24-
member family with a common organisation. Twenty of these proteins have a strongly hydrophobic segment at the NH2-terminal end that could span the lipid bilayer whereas the remaining four, all ofwhich correspond to the seventh gene in their respective operons, mce1E to mce4E, are probably lipoprotein
precursors. In all 24 cases the COOH-terminal domain of themce proteins is predicted to be exposed on the external face of the cytoplasmic
membrane [].The ability to gain entry and resist the antimicrobial intracellular environment of mammalian cells is an essential virulence property of M. tuberculosis. This property is conferred by Mce1A, the third gene of operon 1, which when expressed in E. coli conferred the ability to invade HeLa cells. The recombinant protein when used to coat latex spheres also promoted their uptake into HeLa cells. N terminus deletion constructs of Mce1A identified a domain located between amino acid positions 106 and 163 that was needed for this cell uptake activity. Mce1A contains hydrophobic stretches at the N terminus predictive of a signal sequence, and colloidal gold immunoelectron microscopy indicated that the corresponding native protein is expressed on the surface of M. tuberculosis. Recombinant Mce2A, which had the highest level of identity (67%) to Mce1A, was unable to promote the association of microspheres with HeLa cells and an mce-deletion mutant in Mycobacterium bovis greatly impaired the ability of the microbe to infect epithelial cells in vitro. Although the exact function of Mce1A is still unknown, it appears to serve as an effector molecule expressed on the surface of M. tuberculosis that is capable of eliciting plasma membrane perturbations in non-phagocytic mammalian cells [
]. The distribution of the mce operons in both pathogenic and non-pathogenic mycobacteria suggests that the presence of these putative virulence genes is not an indicator for the pathogenicity of the bacilli - it may be that pathogenicity is determined by their expression [
,
].The members of this family represent all 24 genes associated with the four mammalian cell entry operons of Mycobacterium tuberculosis and their homologues in other Actinomycetales
[].
This family of efflux pump membrane proteins includes EmrA and EmrK [
]. The EmrAB transporter confer resistance to carbonylcyanide m-chlorophenylhydrazone, nalidixic acid, and a number of other toxic compounds []. EmrA is predicted to have a short N-terminal cytoplasmic domain, a single transmembrane helix, and a large periplasmic domain [].
Gram-negative bacteria have evolved transport complexes that export macromolecules and toxic substances such as heavy metals across the two membranes of the cell envelope in a single energy coupled step. The process requires (1) a cytoplasmic membrane export system, (2) a membrane fusion protein (MFP), and (3) an outer membrane factor. Phylogenetic analyses reveal that the MFPs cluster in accordance with the type of cytoplasmic membrane transport systems with which they function - proteins in this family are associated with reisistance to heavy metal poisoning.
Ragulator complex protein LAMTOR3 (for lysosomal adaptor and MAPK and MTOR activator 3) is a regulator of the TOR pathway, which is a signalling cascade that promotes cell growth in response to growth factors, energy levels, and amino acids [
].
F-box/WD repeat-containing protein 2 (FBXW2) is a substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex [
]. It inhibits tumour migration, invasion and metastasis in lung cancer cells by targeting beta-catenin for degradation [].
GRAM domain-containing protein 2A (GRAMD2A) contains a GRAM domain and an ER-anchoring hydrophobic transmembrane domain. It localizes to ER and the plasma membrane (ER-PM) contact sites [
].
Zinc finger protein 106 (Znf106) is an RNA-binding protein that associates with the core splicing factor RNA binding motif protein 39 (RBM39) and localizes to nuclear speckles adjacent to spliceosomes [
]. It is essential for maintenance of peripheral motor neuron and skeletal muscle function [,
].
Bardet-Biedl syndrome (BBS) is a human genetic disorder associated with ciliary dysfunction, resulting in obesity, retinal degeneration, polydactyly, and nephropathy. Twelve BBS genes (BBS1-12) have been identified. BBS6, BBS10, and BBS12 have sequence homology to the CCT (also known as TRiC) family of group II chaperonins. They form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly [
].
The active zone is the presynaptic region in the nerve terminals that mediates neurotransmitter release and is composed a dense collection of proteins called the cytomatrix at the active zone (CAZ). The CAZ proteins are thought to mediate synapse formation and regulate neurotransmitter release [
,
].Bassoon is a CAZ protein that is involved in the formation of the retinal photoreceptor ribbon synapses, which is specialised for tonic release of neurotransmitter in the dark [
]. It plays a partin the early formation and delivery of precursor spheres to nascent ribbon synaptic sites and in ribbon anchoring during later stages of photoreceptor ribbon synaptogenesis [
].This entry represents the first FYVE domain of Protein bassoon, which resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains.
Zinc finger proteins 608 and 609 (ZNF608/ZNF609) are putative transcription factors. ZNF608 represses the expression of ZNF609, which in turn represses recombination-activating gene 1 (Rag1) and Rag2 expression in thymocytes [
]. Interestingly, ZNF609 generates circular RNA (Cir-ZNF609), a novel kind of noncoding RNA that form loop structures without 5'-3' polarities and polyadenylated tails. Cir-ZNF609 has been found to regulate myoblast proliferation and AKT3 expression [,
]. Cir-ZNF609 has also been linked to vascular endothelial dysfunction [].
The cyanobacterial circadian clock protein KaiB is encoded in the kaiABC operon that controls circadian rhythms. It is a component of the KaiABC clock protein complex, which constitutes the main circadian regulator in cyanobacteria [
,
,
]. KaiB has homologues of unknown function in some Archaea and Proteobacteria, and paralogs of unknown function in some Cyanobacteria. KaiB forms homodimers, homotetramers, and multimeric complexes with KaiA and/or KaiC [].
The cyanobacterial circadian clock protein KaiB is encoded in the kaiABC operon that controls circadian rhythms. It is a component of the KaiABC clock protein complex, which constitutes the main circadian regulator in cyanobacteria [
,
]. KaiB forms homodimers, homotetramers, and multimeric complexes with KaiA and/or KaiC [,
]. KaiB-KaiC binding is accompanied by a dramatic reduction in KaiC phosphorylation and followed by dissociation of the clock protein complex [].
Proteins in this family have unknown function. In humans, cartilage acidic protein 1 is expressed in the interterritorial matrix of articular deep zone cartilage [
].
The tsx gene of Escherichia coli encodes an outer membrane protein, Tsx,
which constitutes the receptor for colicin K and Bacteriophage T6, and functions as a substrate-specific channel for nucleosides and deoxy-
nucleosides []. The protein contains 294 amino acids, the first 22 of which are characteristic of a bacterial signal sequence peptide. The putative mature form of Tsx contains 272 residues with a calculated Mr of31418. The Tsx sequence shows an even distribution of charged residues
and lacks extensive hydrophobic stretches []. Tsx shows no significant similarities to the channel-forming proteins OmpC, OmpF, PhoE and LamB from the E. coli outer membrane.
This family of proteins found in operons encoding phosphonate C-P lyase systems as is observed in Escherichia coli [
] and is a member of the metallo-beta-lactamase superfamily (). Instances of this protein are associated with the C-P lyase, but not all genomes containing the C-P lyase system contain phnP.
This entry represents the VP4 coat protein found in Picornaviruses, small RNA-containing mammalian viruses such as Foot-and-mouth disease virus (FMDV) [
], Mengo encephalomyocarditis virus [] and Theiler's murine encephalomyelitis virus (strain DA) (TMEV) []. The viral capsid of Picornaviruses is composed of 60 icosahedral copies of four capsid proteins, VP1, VP2, VP3 and VP4, enclosing the viral positive-strand RNA genome. VP4 lies on the inner surface of the protein shell formed by the major capsid proteins, VP1, VP2 and VP3. The three major capsid proteins have a conserved β-barrel fold, while VP4 has little regular secondary structure. The organisation of the three major capsid proteins leads to surface depressions, or pits, thought to be involved in receptor binding, while the variable outer rim is involved in antibody recognition. The small VP4 is thought to be involved in the initial disassembly and final assembly stages [
].
This family includes Basophilic leukemia-expressed protein Bles03 (also known as UPF0696 protein C11orf68,
) and various uncharacterised proteins of unknown function from eukaryotes, bacteria and archaea. Bles03 shows a two-layer sandwich architecture with a a nine-stranded β-sheet, three α-helices on each side and one solvent-exposed amino-terminal α-helix [
]. This protein has been suggested to have phosphothreonine lyase activity and to play a role in the biosynthesis of dehydro amino acids [].
This entry represents the bactericidal permeability-increasing protein (BPI) and the lipopolysaccharide-binding protein (LBP). The crystal structures of BPI and LBP are similar [
], and they may represent a common gene family of lipid-binding proteins [].In mammals, LBP and BPI mediate the biological effects of LPS (lipopolysaccharide), a glycolipid present in the outer membrane of Gram-negative bacteria. LBP is a plasma protein that enhances the inflammatory response to LPS, whereas BPI is found in lysosomal granules of polymorphonuclear neutrophils, is bactericidal, and neutralises the toxic effects of LPS [
,
]. LBP is an acute phase serum protein secreted mainly by the liver that modulates the LPS-induced immune response. LBP binds mainly to the lipid A moiety of LPS and acts as an affinity enhancer for CD14, facilitating its association with LPS [
].
The cloacin immunity protein complexes with cloacin in equimolar quantities and inhibits it by binding with high affinity to the cloacin C-terminal catalytic domain. The immunity protein is relatively small, containing 85 amino acids.An extra ribosome binding site has been found to precede the immunity gene on the polycistronic Clo DF13 mRNA [
], which perhaps accounts for the fact that, in cloacinogenic cells, more immunity protein than cloacin is synthesised []. Comparison of the complete amino acid sequence of the Clo DF13 immunity protein with that of the Col E3 and Col E6 immunity proteins reveals extensive similarities in primary structure, although Col E3 and Clo DF13 immunity proteins are exchangeable only to a low extent in vivoand
in vitro[
].
Pyocins are polypeptide toxins produced by, and active against, bacteria. S-type pyocins cause cell death by DNA breakdown due to endonuclease activity [
]. Pyocins S1 and S2 are S-type bacteriocins of Pseudomonas aeruginosa with different receptor recognition specificities []. The genetic determinants of these pyocins have been cloned from the NIH-H and PAO chromosomes of P. aeruginosa. The determinants each constitute an operon that encodes two proteins of molecular weight 65,600 and 10,000 (pyocin S1) or 74,000 and 10,000 (pyocin S2) with a characteristic sequence (P box), a possible regulatory element involved in the induction of pyocin production, in the 5' upstream region []. These pyocins have almost identical sequences, except in the N-terminal portions of the large proteins, which are substantially different. This similarity suggests that S1 and S2 pyocins, like pyocin AP41, originated from a common ancestor of the E2 group colicins. Purified pyocins S1 and S2 constitute a complex of the two proteins. Both pyocins cause breakdown of chromosomal DNA and complete inhibition of lipid synthesis in sensitive cells. The large protein (not the complex), shows in vitroDNase activity. This activity is inhibited by the small protein of either pyocin [
].
The Salmonella typhimurium surface presentation of antigens N/invasion
protein J gene (SpaN/InvJ) is one of 12 that form a cluster responsible for invasion properties. The gene product is required for entry by the
bacterium into epithelial cells, and is thus considered to be a virulence factor [
]. Other Spa genes in the cluster are related to invasion (Inv) genes in similar Salmonella and Shigella species [], and to flagella biosynthesis genes in Helicobacter pylori [].Functional analysis of the gene product from SpaN/InvJ has revealed the
protein to have a molecular weight of 36.4kDa []. It is required by the organism to gain access to mammalian epithelial cells, and cellular mutants (InvJ-) fail successfully to infect these cells.It has been found, also, that the inv-spa loci of Salmonella species
encode a type III protein secretion system, essential to the bacterium'shost cell invasion process [
]. Suprisingly, type III-secreted proteinslack the customary signal sequence characteristic of most bacterial
secretory peptides [].
Amyloid protein-binding protein 2 (APPBP2), also known as PAT1, is a microtubule-interacting protein that modulates intracellular transport and processing of amyloid precursor protein (APP), APLP1, and APLP2 [,
].
Matrix remodeling-associated protein 8 (MXRA8), also known as Limitrin or DICAM, is a type I transmembrane protein with two V-type Ig domains in the extracellular region and a short cytoplasmic tail [
]. It is involved in cell-cell adhesion through a heterophilic interaction with alphaVbeta3 integrin [] and acts as a negative regulator of osteoclast differentiation by suppressing the integrin alphaVbeta3 pathway []. It also positively regulates primary cilia and Indian hedgehog signaling, resulting in elongation of long bone []. It has been shown to be a receptor for multiple arthritogenic alphaviruses [].
Centrosomal protein of 131kDa (CEP131) is a cilium-specific protein required for cilium/flagellum formation [
]. In Drosophila, CEP131, also known as Azi1, functions in ciliogenesis and is involved in genome stability and centriole duplication [,
]. In mice, it mediates trafficking events necessary for spermiogenesis and male fertility []. It interacts with BBS4 (Bardet-Biedl syndrome 4) and regulates ciliary trafficking of the BBSome [].
The protein dispatched homolog 3 (DISP3) is a sterol-sensing domain-containing protein that promotes cell proliferation and alters expression of genes that are involved in tumorigenesis [
]. It has also been shown to influence neural stem cell fate decisions [].
This family belongs to the larger set of probable enzymes modeled by
. Members are found primarily in the Actinobacteria (Mycobacterium, Streptomyces, etc.). The family is uncharacterised.
This family belongs to the larger set of probable enzymes defined by
. Members are found primarily in the Actinobacteria (Mycobacterium, Streptomyces, etc.). The family is uncharacterised.
This family belongs to the larger set of probable enzymes defined by
. Members are found primarily in the Actinobacteria (Mycobacterium, Streptomyces, etc.). The family is uncharacterised.
Asp23 was identified as an alkaline shock protein expressed in a sigmaB-dependent manner in Staphylococcus aureus (
) [
]. Following an alkaline shock, Asp23 accumulates in the soluble protein fraction of the S. aureus cell. Asp23 is one of the most abundant proteins in the cytosolic protein fraction of stationary S. aureus cells, with a copy-number of >25000 per cell. It is linked to the staphylococcal cell membrane and anchored there by AmpA. The overall function for the family is thus a cell envelope-related one in Gram-positive bacteria. [
].
This protein family is found, so far, only in the Actinobacteria (Streptomyces, Mycobacterium, Corynebacterium, Nocardia, Propionibacterium, etc.) and never more than one to a genome. Members show twilight-level sequence similarity to family of AMP-binding enzymes described by
.
YaaA is a key element of the stress response to H2O2. It acts by reducing the level of intracellular iron levels after peroxide stress, thereby attenuating the Fenton reaction and the DNA damage that this would cause [
]. The molecular mechanism of action is not known.
This family contains MukF, which are proteins involved in chromosome condensation, segregation and cell cycle progression. MukE along with MukF interact with MukB in vivo forming a complex, which is required for chromosome condensation and segregation in Escherichia coli [
]. The Muk complex appears to be similar to the SMC-ScpA-ScpB complex in other prokaryotes where MukB is the homologue of SMC []. ScpA and ScpB have little sequence similarity to MukE or MukF, though they are predicted to be structurally similar, being predominantly α-helical with coiled coil regions. The structure of MuKF has been revealed [].
FBXW5 is a F-box protein and a DDB1-binding WD40 (DWD) protein that serves as a substrate recognition component of both SCF (SKP1-CUL1-F-box protein) and DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes [
,
]. It has also been shown to negatively regulate TAK1 MAP3K in the IL-1beta signaling pathway []. Interestingly, FBXW5 binds centriolar protein HsSAS-6 and promotes its ubiquitylation; this way FBXW5 can restrict centrosome re-duplication through degradation of HsSAS-6 [].
This entry represents a domain found in the human PiggyBac transposable element-derived proteins (PGBDs) and some uncharacterised proteins. Its function is not clear.
This entry refers to Tetratricopeptide repeat protein 26 (TTC26, also known as Intraflagellar transport protein 56).TTC26 is required for ciliogenesis and normal cilia function in zebrafish [
]. A mutation in the mouse TTC26 gene leads to impaired hedgehog signalling and causes hop-sterile (hop), which is characterised by a hopping gait, polydactyly, hydrocephalus, and male sterility []. Mouse TTC26 binds directly to the Ift46 subunit of Intraflagellar Transport (IFT) complex B, however, the TTC26 defect does not result in a decrease in the number or length of primary cilia [].
This entry represents the major capsid protein found in bacteriophages. Major capsid protein assembles to form an icosahedral capsid with a T=7 symmetry [
,
]. It plays a role in the stabilisation of the condensed form of the DNA molecule in phage heads [].This protein is also found in bacteria, suggesting prophage matches also occur.
DNA repair protein XRCC2 is a RAD51 paralogue. In humans, it is part of the protein complex BCDX2 (contains RAD51B, RAD51C, RAD51D, and XRCC2), which acts in the BRCA1-BRCA2-dependent homologous recombination pathway [
,
]. Upon DNA damage, BCDX2 acts downstream of BRCA2 recruitment and upstream of RAD51 recruitment. BCDX2 bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA []. Interestingly, XRCC2 and other homologous recombination proteins are associated with centrosomes and are required for mitotic stability [].
This iron-sulphur protein is found in a contiguous genomic region with subunits of cytochrome b558/566, and appears to be part of a cytochrome bc1-analogous system [
].
The CRISPR-Cas system is a prokaryotic defense mechanism against foreign genetic elements. The key elements of this defense system are the Cas proteins and the CRISPR RNA. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are a family of DNA direct repeats separated by regularly sized non-repetitive spacer sequences that are found in most bacterial and archaeal genomes [
]. CRISPRs appear to provide acquired resistance against mobile genetic elements (viruses, transposable elements and conjugative plasmids). CRISPR clusters contain sequences complementary to antecedent mobile elements and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA).The defense reaction is divided into three stages. In the adaptation stage, the invader DNA is cleaved, and a piece of it is selected to be integrated as a new spacer into the CRISPR locus, where it is stored as an identity tag for future attacks by this invader. During the second stage (the expression stage), the CRISPR RNA (pre-crRNA) is transcribed and subsequently processed into the mature crRNAs. In the third stage (the interference stage), Cas proteins, together with crRNAs, identify and degrade the invader [
,
,
].The CRISPR-Cas systems have been sorted into three major classes. In CRISPR-Cas types I and III, the mature crRNA is generally generated by a member of the Cas6 protein family. Whereas in system III the Cas6 protein acts alone, in some class I systems it is part of a complex of Cas proteins known as Cascade (CRISPR-associated complex for antiviral defense). The Cas6 protein is an endoribonuclease necessary for crRNA production whereas the additional Cas proteins that form the Cascade complex are needed for crRNA stability [
]. This entry represents the Csc3 family of Cas proteins that are strictly associated with the Cyano subtype of CRISPR/Cas locus, found in several species of Cyanobacteria and several archaeal species. This family is designated Csc3 for CRISPR/Cas Subtype Cyano protein 3, as it is often the third gene upstream of the core cas genes, cas3-cas4-cas1-cas2 [
].
Patatin-like phospholipase domain-containing protein
Type:
Family
Description:
This entry includes patatin-like phospholipase domain-containing proteins 1-5 (PNPLA1-5) from humans and Atgl-1 from Caenorhabditis elegans. They are a group of lipid hydrolases. Atgl-1 may play a role in the response of the organism to starvation, enhancing hydrolysis of triglycerides and providing free fatty acids to other tissues to be oxidized in situations of energy depletion [
,
,
,
,
,
]. In humans PNPLA1 has a role in the formation of the epidermal lipid barrier; mutations in this gene are associated with the skin disorder known as ichthyosis [
]. PNPLA1 acts as an omega-hydroxyceramide transacylase involved in the synthesis of omega-O-acylceramides (esterified omega-hydroxyacyl-sphingosine; EOS), which are extremely hydrophobic lipids involved in skin barrier formation [,
]. It catalyzes the last step of the synthesis of omega-O-acylceramides by transferring linoleic acid from triglycerides to an omega-hydroxyceramid [].Human PNPLA2 catalyses the initial step in triglyceride hydrolysis in adipocyte and non-adipocyte lipid droplets [
]. PNPLA3 has both triacylglycerol lipase and acylglycerol O-acyltransferase activities [].
The family includes RNF121, RNF175 and similar proteins. RNF121 is an E3-ubiquitin ligase present in the endoplasmic reticulum (ER) and cis-Golgi compartments. It is a novel regulator of apoptosis [
]. It also facilitates the degradation and membrane localization of voltage-gated sodium (NaV) channels, and thus plays a role in the quality control of NaV channels during their synthesis and subsequent transport to the membrane []. Moreover, RNF121 acts as a broad regulator of nuclear factor kappaB (NF-kappaB) signaling since its silencing also dampens NF-kappaB activation following stimulation of toll-like receptors (TLRs), nod-like receptors (NLRs), RIG-I-like Receptors (RLRs) or after DNA damages []. RNF121 contains five conserved transmembrane (TM) domains and a C3H2C2-type RING-H2 finger. RNF175 is an uncharacterized RING finger protein that shows high sequence similarity with RNF121.
This domain, found in sex-determining protein Xol-1, adopts a secondary structure consisting of five alpha helices and six antiparallel beta sheets, in a beta-α-β-β-β-α-β-α-α-α-β arrangement. The fold of this family is similar to that found in ribosomal protein S5 domain 2-like [
]. The active site of the enzyme is found at the interface between this domain and the C-terminal GHMP-like domain.
This domain, found in sex-determining protein Xol-1, adopts a secondary structure consisting of five alpha helices and seven antiparallel beta sheets, in a beta-α-β-α-α-α-β-beta-α-β-β-β arrangement. The fold of this family is structurally similar to that found in the C-terminal domain of GHMP Kinase [
]. The active site of the enzyme is found at the interface between this domain and the N-terminal domain.
The family of type 2 integral membrane protein (ITM2) consists of three members, ITM2A, ITM2B and ITM2C [
]. Members of this family contain a BRICHOS domain, which possesses chaperone activity [,
].ITM2A is a target gene of GATA-3, a T cell-specific transcription factor [
].ITM2B is proteolytically cleaved at three locations; cleavage by furin in the C-terminal region generates a 23-residue peptide (ABri23), processing by ADAM10 results in release of the BRICHOS domain from the membrane-bound N-terminal part and intramembrane cleavage by SPPL2a/2b liberates the intracellular domain [
]. ITM2B (BRI2) is a target of BCL6 transcriptional repression and a short form of the ITM2B protein, similarly to other targets of BCL6, induces apoptosis in hematopoietic cell lines []. ITM2B interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production [,
]. ITM2C (BRI3) also inhibits amyloid precursor protein processing, but through a different mechanism to ITM2B [].
Proteins in this family, designated mobile mystery protein B, are more often encoded within mobilisation-related contexts than not. This includes a CRISPR-associated gene region in Geobacter sulfurreducens PCA, and plasmids in Agrobacterium tumefaciens and Coxiella burnetii. They are always found together with mobile mystery protein A (
), a helix-turn-helix putative DNA binding protein. This protein is encoded by the downstream member of the gene pair and belongs to the Fic protein family, where Fic (filamentation induced by cAMP) is a regulator of cell division. The characteristics of having a two-gene operon in a varied context, often on plasmids, with one member affecting cell division and the other able to bind DNA, suggests similarity to addiction modules.
Proteins in this family are from eukaryotes and contain a CUE domains. Human CUE domain-containing protein 1 (CUEDC1) is uncharacterized, but its tertiary structure has been solved (
).
EF-hand domain-containing protein EFHC1/EFHC2/EFHB
Type:
Family
Description:
This entry represents a group of EF-hand domain-containing proteins, including EFHC1, EFHC2 and EFHB. EFHC1 has been shown to interact with microtubules to regulate cell division and cortical development [
]. Mutations in the EFHC1 gene has been linked to juvenile myoclonic epilepsy []. The function of EFHC2 and EFHB is not clear.
Minichromosome maintenance protein 10 (Mcm10) is a eukaryotic DNA replication factor that regulates the stability and chromatin association of DNA polymerase alpha [
]. It is required for DNA synthesis and for entry into or completion of S phase. It is associated with the DNA polymerase-alpha (pol-alpha) primase complex throughout the cell cycle, and is a nuclear chaperone for Cdc17, which is otherwise rapidly degraded []. It is also required for maintenance of transcriptional silencing [].
This entry includes OCIA domain-containing protein 1/2 (OCAD1/2). OCAD1 is involved in integrin-mediated cancer cell adhesion and colony formation in ovarian cancer [
]. The function of OCAD2 is not clear.
This family contains THUMP domain-only proteins including THUMP domain-containing protein 1 and Saccharomyces cerevisiae Tan1. Tan1 is non essential and has been shown to be required for the formation of the modified nucleoside N(4)-acetylcytidine (ac(4)C) in tRNA. THUMPD1 is also an adapter required for NAT10-dependent tRNA acetylation [
]. The THUMP domain is named after thiouridine synthases, methylases and PSUSs. The domain consists of about 110 amino acid residues. It is predicted to be an RNA-binding domain and probably functions by delivering a variety of RNA modification enzymes to their targets [,
,
].
This entry represents JDP1, also known as DnaJ homologue subfamily C member 12 (DNAJC12), which is a J domain-containing protein with unknown function [
]. Its expression in breast cancer cells is associated with its estrogen receptor status [].
