This family of proteins is found in bacteria. Proteins in this family are typically between 215 and 413 amino acids in length. There is a conserved DSNGYS sequence motif.
Neuronatin is involved in brain development [
] and may participate in the maintenance of segment identity in the hindbrain and pituitary development, and maturation or maintenance of the overall structure of the nervous system [].
This family consists of several hypothetical bacterial proteins of unknown function. This family was recently identified as belonging to the nucleotidyltransferase superfamily [
].
Type III restriction/modification enzyme methylation subunit
Type:
Domain
Description:
This domain family is found in bacteria, and is approximately 60 amino acids in length. It is found in association with
. There are two completely conserved residues (F and S) that may be functionally important. It is found in bacterial phage resistance proteins, in particular in the methylation subunit of the type III restriction/modification enzyme complex [
].
Bone marrow stromal antigen 2, also known as tetherin, is an antiretroviral defence protein, that blocks release of enveloped virus from the cell surface [
,
,
]. Bst2/tetherin contains two membrane anchors which are employed to retain some enveloped viruses, including HIV-1, tethered to the plasma membrane in the absence of virus encoded antagonists []. Its expression is induced by interferon-alpha [] and was originally linked to B cell development [].
Neurensin-1 is a vesicular membrane protein expressed exclusively in brain that may play an important role in vesicular organelles transport and nerve signals [
]. Neurensin-2 is also expressed in neural cells, but with a different intracellular localisation: neurensin-1 was found mainly in neuritic processes, while neurensin-2 is found in cell bodies [].
N-acyl-phosphatidylethanolamine-hydrolysing phospholipase D
Type:
Family
Description:
N-acyl-phosphatidylethanolamine-hydrolysing phospholipase D (NAPE-PLD) hydrolyzes N-acyl-phosphatidylethanolamines (NAPEs) to produce N-acylethanolamines (NAEs) [
]. It is responsible for the generation of the NAE anandamide, the ligand of cannabinoid and vanilloid receptors []. Although predominantly bacterial, a mitochondrial form exists []. NAPE-PLD belongs to the metallo-beta-lactamase family [].
This family is found in bacteria and viruses, and is approximately 160 amino acids in length. Some annotation suggests that it may be a tail fibre protein. There are two completely conserved residues (K and W) in these proteins that may be functionally important.
Ashwin is a developmental protein that is expressed in the neural plate, and later in the embryonic brain, eyes, and spinal cord [
]. It may be involved in the regulation cell survival and anteroposterior patterning. Ashwin has been shown to form a complex with HSPC117, which is a catalytic subunit of the tRNA-splicing ligase complex [].
This entry represents a domain found in bacterial proteins of unknown function. The crystal stucture has been solved for a protein containing this domain
[
].
The name LSPD derives from the conserved residues in the middle of the repeat. These repeats are found in coagulation factor V and occur in the B domain, which is cleaved prior to activation of the protein. It has been suggested that domain B bring domains A and C together for activation [
].Coagulation factor V is a central regulator of hemostasis and serves as a critical cofactor for the prothrombinase activity of factor Xa that results in the activation of prothrombin to thrombin.
In some species, histidine utilisation goes via urocanate to glutamate in four step, the last being removal of formamide. This entry describes an alternate fourth step, formimidoylglutamate deiminase which leads to N-formyl-L-glutamate [
,
]. This product may be acted on by formylglutamate amidohydrolase () and bypass glutamate as a product during its degradation. Alternatively, removal of formate (by
) would yield glutamate.
A number of plant and fungal proteins that bind N-acetylglucosamine (e.g. solanaceous lectins of tomato and potato, plant endochitinases, the wound-induced proteins: hevein, win1 and win2, and the Kluyveromyces lactis killer toxin alpha subunit) contain this domain [
]. The domain may occur in one or more copies and is thought to be involved in recognition or binding of chitin subunits [,
]. In chitinases, as well as in the potato wound-induced proteins, the 43-residue domain directly follows the signal sequence and is therefore at the N terminus of the mature protein; in the killer toxin alpha subunit it is located in the central section of the protein.
The Src homology 2 (SH2) domain is a protein domain of about 100 amino-acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps [
]. Similar sequences were later found in many other intracellular signal-transducing proteins []. SH2 domains function as regulatory modules of intracellular signalling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific, SH2 domains recognise between 3-6 residues C-terminal to the phosphorylated tyrosine in a fashion that differs from one SH2 domain to another, and strictly phosphorylation-dependent manner [
,
,
,
]. They are found in a wide variety of protein contexts e.g., in association with catalytic domains of phospholipase Cy (PLCy) and the non-receptor protein tyrosine kinases; within structural proteins such as fodrin and tensin; and in a group of small adaptor molecules, i.e Crk and Nck. The domains are frequently found as repeats in a single protein sequence and will then often bind both mono- and di-phosphorylated substrates.
The structure of the SH2 domain belongs to the α+β class, its overall shape forming a compact flattened hemisphere. The core structural elements comprise a central hydrophobic anti-parallel β-sheet, flanked by 2 short α-helices. The loop between strands 2 and 3 provides many of the binding interactions with the phosphate group of its phosphopeptide ligand, and is hence designated the phosphate binding loop, the phosphorylated ligand binds perpendicular to the β-sheet and typically interacts with the phosphate binding loop and a hydrophobic binding pocket that interacts with a pY+3 side chain. The N- and C-termini of the domain are close together in space and on the opposite face from the phosphopeptide binding surface and it has been speculated that this has facilitated their integration into surface-exposed regions of host proteins [
].
Photosystem II reaction centre protein H superfamily
Type:
Homologous_superfamily
Description:
Oxygenic photosynthesis uses two multi-subunit photosystems (I and II) located in the cell membranes of cyanobacteria and in the thylakoid membranes of chloroplasts in plants and algae. Photosystem II (PSII) has a P680 reaction centre containing chlorophyll 'a' that uses light energy to carry out the oxidation (splitting) of water molecules, and to produce ATP via a proton pump. Photosystem I (PSI) has a P700 reaction centre containing chlorophyll that takes the electron and associated hydrogen donated from PSII to reduce NADP+ to NADPH. Both ATP and NADPH are subsequently used in the light-independent reactions to convert carbon dioxide to glucose using the hydrogen atom extracted from water by PSII, releasing oxygen as a by-product.PSII is a multisubunit protein-pigment complex containing polypeptides both intrinsic and extrinsic to the photosynthetic membrane [
,
,
]. Within the core of the complex, the chlorophyll and beta-carotene pigments are mainly bound to the antenna proteins CP43 (PsbC) and CP47 (PsbB), which pass the excitation energy on to the reaction centre proteins D1 (Qb, PsbA) and D2 (Qa, PsbD) that bind all the redox-active cofactors involved in the energy conversion process. The PSII oxygen-evolving complex (OEC) oxidises water to provide protons for use by PSI, and consists of OEE1 (PsbO), OEE2 (PsbP) and OEE3 (PsbQ). The remaining subunits in PSII are of low molecular weight (less than 10kDa), and are involved in PSII assembly, stabilisation, dimerisation, and photo-protection []. This superfamily represents the low molecular weight phosphoprotein PsbH found in PSII. The phosphorylation site of PsbH is located in the N terminus, where reversible phosphorylation is light-dependent and redox-controlled. PsbH is necessary for the photoprotection of PSII, being required for: (1) the rapid degradation of photodamaged D1 core protein to prevent further oxidative damage to the PSII core, and (2) the insertion of newly synthesised D1 protein into the thylakoid membrane []. PsbH may also regulate the transfer of electrons from D2 (Qa) to D1 (Qb) in the reaction core.
Integrase comprises three domains capable of folding independently and whose three-dimensional structures are known. However, the manner in which the N-terminal, catalytic core, and C-terminal domains interact in the holoenzyme remains obscure. Numerous studies indicate that the enzyme functions as a multimer, minimally a dimer. The integrase proteins from Human immunodeficiency virus 1 (HIV-1) and Avian sarcoma virus (have been studied most carefully with respect to the structural basis of catalysis. Although the active site of avian virus integrase does not undergo significant conformational changes on binding the required metal cofactor, that of HIV-1 does. This active site-mediated conformational change in HIV-1 reorganises the catalytic core and C-terminal domains and appears to promote an interaction that is favourable for catalysis []. Retroviral integrase is synthesised as part of the POL polyprotein that contains; an aspartyl protease, a reverse transcriptase, RNase H and integrase. POL polyprotein undergoes specific enzymatic cleavage to yield the mature proteins. The presence of retrovirus integrase-related gene sequences in eukaryotes is known. Bacterial transposases involved in the transposition of the insertion sequence also belong to this group. HIV-1 integrase catalyses the incorporation of virally derived DNA into the human genome. This unique step in the virus life cycle provides a variety of points for intervention and hence is an attractive target for the development of new therapeutics for the treatment of AIDS [
]. Substrate recognition by the retroviral integrase enzyme is critical for retroviral integration. To catalyse this recombination event, integrase must recognise and act on two types of substrates, viral DNA and host DNA, yet the necessary interactions exhibit markedly different degrees of specificity [].
The CRAL-TRIO domain is a protein structural domain that binds small lipophilic molecules [
]. The domain is named after cellular retinaldehyde-binding protein (CRALBP) and TRIO guanine exchange factor.The CRAL-TRIO domain is found in GTPase-activating proteins (GAPs), guanine nucleotide exchange factors (GEFs) and a family of hydrophobic ligand binding proteins, including the yeast SEC14 protein and mammalian retinaldehyde- and alpha-tocopherol-binding proteins. The domain may either constitute all of the protein or only part of it [
,
,
,
].The structure of the domain in SEC14 proteins has been determined [
]. The structure contains several alpha helices as well as a beta sheet composed of 6 strands. Strands 2,3,4 and 5 form a parallel beta sheet with strands 1 and 6 being anti-parallel. The structure also identified a hydrophobic binding pocket for lipid binding.
This superfamily includes the beta (or middle) subunit of the oligomeric (alpha2beta2gamma2) diol dehydratases (DDH) and glycerol dehydratases (GDH), which are enzymes produced by some enterobacteria, as well as the beta subunit of the tetrameric (alpha2beta2) glycerol dehydratase reactivase, which removes damaged coenzyme B12 from GDH that has suffered mechanism-based inactivation [,
]. The beta subunit of GDH reactivase resembles that of GDH and DDH, displaying a three-layer α/β/α fold, except that the reactivase subunit lacks some B12-binding elements.
The N-terminal region of a number of fungal transcriptional regulatory proteins contains a Cys-rich motif that is involved in zinc-dependent binding of DNA. The region forms a binuclear Zn cluster, in which two Zn atoms are bound by six Cys residues [,
]. A wide range of proteins are known to contain this domain. These include the proteins involved in arginine, proline, pyrimidine, quinate, maltose and galactose metabolism, amide and GABA catabolism, leucine biosynthesis, amongst others.
Unique short glycoprotein 2 (US2) and US3 are Herpesviral proteins that interfere with the expression of major histocompatibility complex (MHC) class I molecules on the surface of infected cells. US2 is an endoplasmic reticulum resident transmembrane protein that binds to newly synthesized MHC class I heavy chains in the endoplasmic reticulum, redirecting them to the cytosol for proteasome-dependent destruction, thereby preventing their expression at the cell surface [
]. US3 is similarly an endoplasmic reticulum resident transmembrane glycoprotein that binds MHC class I molecules and prevents their departure. The endoplasmic reticulum retention signal of the US3 protein is contained in the luminal domain of the protein [].
Proteins containing this domain are similar to L-fucose isomerase expressed by Escherichia coli (
,
). This enzyme corresponds to glucose-6-phosphate isomerase in glycolysis, and converts an aldo-hexose to a ketose to prepare it for aldol cleavage. The enzyme is a hexamer, with each subunit being wedge-shaped and composed of three domains. Both domains 1 and 2 contain central parallel beta- sheets with surrounding alpha helices. The active centre is shared between pairs of subunits related along the molecular three-fold axis, with domains 2 and 3 from one subunit providing most of the substrate-contacting residues [
].
Aldehyde oxidase (
) catalyses the conversion of an aldehyde in the presence of oxygen and water to an acid and hydrogen peroxide. The enzyme is a homodimer, and requires FAD, molybdenum and two 2FE-2S clusters as cofactors. Xanthine dehydrogenase (
) catalyses the hydrogenation of xanthine to urate, and also requires FAD, molybdenum and two 2FE-2S clusters as cofactors. This activity is often found in a bifunctional enzyme with xanthine oxidase (
) activity too. The enzyme can be converted from the dehydrogenase form to the oxidase form irreversibly by proteolysis or reversibly through oxidation of sulphydryl groups.
The aldehyde oxidase and xanthine dehydrogenase, a/b hammerhead domain is an evolutionary conserved protein domain [
,
]. The core structure of this domain has a β-β-α-β-BETA-beta-alpha fold and contains a β-hammerhead motif similar to that in barrel-sandwich hybrids.
This family consists of several Chordopoxvirus A33R proteins. A33R plays a role in promoting Ab-resistant cell-to-cell spread of virus [
] and interacts with A36R to incorporate the protein into the outer membrane of intracellular enveloped virions (IEV) [].
Proteins containing this domain are similar to L-fucose isomerase expressed by Escherichia coli (
,
). This enzyme corresponds to glucose-6-phosphate isomerase in glycolysis, and converts an aldo-hexose to a ketose to prepare it for aldol cleavage. The enzyme is a hexamer, with each subunit being wedge-shaped and composed of three domains. Both domains 1 and 2 contain central parallel β-sheets with surrounding alpha helices. Domain 1 demonstrates the beta-α-β-α-β Rossman fold. The active centre is shared between pairs of subunits related along the molecular three-fold axis, with domains 2 and 3 from one subunit providing most of the substrate-contacting residues, and domain 1 from the adjacent subunit contributing some other residues [
].
Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [
,
,
,
,
]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few []. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target. This entry represents C-x8-C-x5-C-x3-H (CCCH) type Zinc finger (Znf) domains superfamily. Proteins containing CCCH Znf domains include Znf proteins from eukaryotes involved in cell cycle or growth phase-related regulation, e.g. human TIS11B (butyrate response factor 1), a probable regulatory protein involved in regulating the response to growth factors, and the mouse TTP growth factor-inducible nuclear protein, which has the same function. The mouse TTP protein is induced by growth factors. Another protein containing this domain is the human splicing factor U2AF 35kDa subunit, which plays a critical role in both constitutive and enhancer-dependent splicing by mediating essential protein-protein interactions and protein-RNA interactions required for 3' splice site selection. It has been shown that different CCCH-type Znf proteins interact with the 3'-untranslated region of various mRNA [
,
]. This type of Znf is very often present in two copies.
This family consists of the Bacillus species-specific PapR protein. The papR gene belongs to the PlcR regulon and is located 70 bp downstream from plcR. It encodes a 48-amino-acid peptide. Disruption of the papR gene abolishes expression of the PlcR regulon, resulting in a large decrease in haemolysis and virulence in insect larvae. A processed form of PapR activates the PlcR regulon by allowing PlcR to bind to its DNA target. This activating mechanism is strain specific [
].
In eukaryotes, cyclin-dependent protein kinases interact with cyclins to regulate cell cycle
progression, and are required for the G1 and G2 stages of cell division []. Theproteins bind to a regulatory subunit, cyclin-dependent kinase regulatory subunit (CKS),
which is essential for their function. This regulatory subunit is a small protein of 79 to 150residues. In yeast (gene CKS1) and in fission yeast (gene suc1) a single isoform is known,
while mammals have two highly related isoforms. The regulatory subunits exist as hexamers,formed by the symmetrical assembly of 3 interlocked homodimers, creating an unusual
12-stranded β-barrel structure []. Through the barrel centre runs a 12A diametertunnel, lined by 6 exposed helix pairs [
]. Six kinase units can be modelled to bind thehexameric structure, which may thus act as a hub for cyclin-dependent protein kinase
multimerisation [,
].
This entry represents HrpB, one of two related predicted DEAH-box ATP-dependent helicases of unknown function found in many proteobacteria, but also in a few species of other lineages. The member from Rhizobium meliloti (Sinorhizobium meliloti), designated HelO, has been studied but is not essential for growth and mutants have no obvious phenotype [
]. HrpB is typically about 800 residues in length, while its paralog HrpA (), also uncharacterised, is about 1300 amino acids long. Related characterised eukaryotic proteins are RNA helicases associated with pre-mRNA processing [
].
Thyroglobulin (Tg) is a large glycoprotein specific to the thyroid gland and is the precursor of the iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3). The N-terminal section of Tg contains 10 repeats of a domain of about 65 amino acids which is known as the Tg type-1 repeat [
,
]. Such a domain has also been found as a single or repeated sequence in the HLA class II associated invariant chain []; human pancreatic carcinoma marker proteins GA733-1 and GA733-2 []; nidogen (entactin), a sulphated glycoprotein which is widely distributed in basement membranes and that is tightly associated with laminin; insulin-like growth factor binding proteins (IGFBP) []; saxiphilin, a transferrin-like protein from Rana catesbeiana (Bull frog) that binds specifically to the neurotoxin saxitoxin []; chum salmon egg cysteine proteinase inhibitor, and equistatin, a thiol-protease inhibitor from Actinia equina (sea anemone) []. The existence of Thyr-1 domains in such a wide variety of proteins raises questions about their activity and function, and their interactions with neighbouring domains. The Thyr-1 and related domains belong to MEROPS proteinase inhibitor family I31, clan IX.Equistatin from A. equina is composed of three Thyr-1 domains; as with other proteins that contains Thyr-1 domains, the thyropins, they bind reversibly and tightly to cysteine proteases (inhibitor family C1). In equistatin inhibition of papain is a function of domain-1. Unusually domain-2 inhibits cathepsin D, an aspartic protease (inhibitor family A1) and has no activity against papain. Domain-3, does not inhibit either papain or cathepsin D, and its function or its target peptidase has yet to be determined [
,
].The thyroglobulin type-1 domain has an alpha+beta fold.
Cytoskeleton-associated proteins (CAPs) are involved in the organisation of microtubules and transportation of vesicles and organelles along the cytoskeletal network. A conserved glycine-rich domain, CAP-Gly, has been identified in a number of CAPs, including CLIP-170 and dynactins. The crystal structure of the Caenorhabditis elegans F53F4.3 protein CAP-Gly domain has been solved. The domain contains three β-strands. The most conserved sequence, GKNDG, is located in two consecutive sharp turns on the surface, forming the entrance to a groove [].
Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation which is usually zinc, but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophillic role. Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site [
]. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [].This group of proteins include metallopeptidases belonging to the MEROPS peptidase family M38 (clan MJ, beta-aspartyl dipeptidase family).
This entry includes the beta-aspartyl dipeptidase from Escherichia coli, (, IadA; MEROPS identifier M38.001), which degrades isoaspartyl dipeptides and may unblock degradation of proteins that cannot be repaired. This entry also describes closely related proteins from other species (e.g. Clostridium perfringens, Thermoanaerobacter tengcongensis) that may have an equivalent in function. This family shows homology to dihydroorotases.
The L-isoaspartyl derivative of Asp arises non-enzymatically over time as a form of protein damage. In this isomerisation, the connectivity of the polypeptide changes to pass through the β-carboxyl of the side chain. Much but not all of this damage can be repaired by protein-L-isoaspartate (D-aspartate) O-methyltransferase.
Isoaspartyl dipeptidase (MEROPS identifier M38.001) hydrolyzes the β-L-isoaspartyl linkages in dipeptides, as part of the degradative pathway to eliminate proteins with β-L-isoaspartyl peptide bonds, bonds whereby the β-group of an aspartate forms the peptide link with the amino group of the following amino acid. Formation of this bond is a spontaneous nonenzymatic reaction in nature and can profoundly affect the function of the protein. Isoaspartyl dipeptidase is an octameric enzyme that contains a binuclear zinc centre in the active site of each subunit and shows a strong preference of hydrolyzing Asp-Leu dipeptides [
].
Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP. There are several different types of transmembrane ATPases, which can differ in function (ATP hydrolysis and/or synthesis), structure (e.g., F-, V- and A-ATPases, which contain rotary motors) and in the type of ions they transport [
,
]. The different types include:F-ATPases (ATP synthases, F1F0-ATPases), which are found in mitochondria, chloroplasts and bacterial plasma membranes where they are the prime producers of ATP, using the proton gradient generated by oxidative phosphorylation (mitochondria) or photosynthesis (chloroplasts).V-ATPases (V1V0-ATPases), which are primarily found in eukaryotes and they function as proton pumps that acidify intracellular compartments and, in some cases, transport protons across the plasma membrane [
]. They are also found in bacteria [].A-ATPases (A1A0-ATPases), which are found in Archaea and function like F-ATPases, though with respect to their structure and some inhibitor responses, A-ATPases are more closely related to the V-ATPases [
,
].P-ATPases (E1E2-ATPases), which are found in bacteria and in eukaryotic plasma membranes and organelles, and function to transport a variety of different ions across membranes.E-ATPases, which are cell-surface enzymes that hydrolyse a range of NTPs, including extracellular ATP.F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (
) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the alpha(3)beta(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis [
]. These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.In yeast, the F0 complex is composed of at least nine polypeptides which are nucleus-encoded: b, OSCP, d, e, f, g, h, i/j and k, together with three subunits, 6, 8 and 9, which are mitochondrion-encoded. The bovine enzyme also includes subunit F6 for which no homologue has been found in yeast [
].This entry represents subunit 8 found in the F0 complex of mitochondrial F-ATPases from fungi. This subunit appears to be an integral component of the stator stalk in yeast mitochondrial F-ATPases [
]. The stator stalk is anchored in the membrane, and acts to prevent futile rotation of the ATPase subunits relative to the rotor during coupled ATP synthesis/hydrolysis. This subunit differs in sequence between fungi, Metazoa () and plants (
).
This entry consists of several Chloride channel CLIC-like proteins, which function as a chloride channel when incorporated in the planar lipid bilayer [
].
This region at the C terminus of the APC proteins binds the microtubule-associating protein EB-1 [
]. At the C terminus of the alignment is also a PDZ-binding domain. A short motif in the middle of the region appears to be found in the APC2 proteins (e.g. ).
Competence is the ability of a cell to take up exogenous DNA from its environment, resulting in transformation. It is widespread among bacteria and is probably an important mechanism for the horizontal transfer of genes. DNA usually becomes available by the death and lysis of other cells. Competent bacteria use components of extracellular filaments called type 4 pili to create pores in their membranes and pull DNA through the pores into the cytoplasm. This process, including the development of competence and the expression of the uptake machinery, is regulated in response to cell-cell signalling and/or nutritional conditions [
].Natural genetic competence in Bacillus subtilis is controlled by quorum-sensing (QS). The ComP- ComA two-component system detects the signalling molecule ComX, and this signal is transduced by a conserved phosphotransfer mechanism. ComX is synthesised as an inactive precursor and is then cleaved and modified by ComQ before export to the extracellular environment [
].
This domain family is found in bacteria and eukaryotes, and is approximately 50 amino acids in length. The family is found in association with
,
. There is a single completely conserved residue W that may be functionally important. PHBC is the third enzyme of the poly-beta-hydroxybutyrate biosynthetic pathway.
Maf transcription factors form a distinct subfamily of the basic leucine zipper (bZip) transcription factors [
]. Maf genes have been identified in a wide range of higher eukaryotes, including both vertebrate and invertebrate species. These proteins are unique among the bZip factors in that they contain a highly conserved extended homology region (EHR), or ancillary DNA binding region, in addition to a typical basic region, and both regions are involved in target DNA sequence recognition. Maf transcription factors regulate tissue-specific gene expression and cell-differentiation in a wide variety of tissues and are also involved in human diseases and oncogenic transformation. Tissue-specific expression invloves Maf binding to Maf-recognition elements (MAREs) in the regulatory regions of target genes, and interacting with other transcription factors.
This region of the APC family of proteins is known as the basic domain. It contains a high proportion of positively charged amino acids and interacts with microtubules [
].
This domain is approximately 80 amino acids in length and is found in yeast transcriptional activators such as MSN1 [
], GCR1 [] and osmostress-induced transcription factor Hot1 [].
This domain family is found in bacteria, and is approximately 50 amino acids in length. There is a single completely conserved residue Y that may be functionally important.
Hexamethylene bisacetamide-inducible proteins (HEXIMs) are transcriptional regulators that function as general RNA polymerase II transcription inhibitors. HEXIMs, aided by the 7SK snRNA, sequester positive transcriptional elongation factor b (P-TEFb) into a large inactive 7SK snRNP complex [
,
]. This prevents P-TEFb from phosphorylating RNA polymerase II and blocks subsequent transcriptional elongation.Two HEXIM family members have been identified in mammals, termed HEXIM1 and HEXIM2, which exhibit distinct expression patterns [
].
The major components of the vaccinia virus membrane consists of the A17L, A14L, A13L, L1L, D8R, and H3L proteins. This entry represents the A13L protein, which is 70 amino acids long and has an N-terminal hydrophobic region that is implicated in cotranslational insertion of the protein into the membranes of the ER. It is dispensable for the early biogenesis of the virion membrane but is essential for virion maturation [
].
This domain family is found in bacteria, and is approximately 50 amino acids in length. This domain is found at the C-terminal of SteA proteins from Corynebacterium [
]. SteA and SteB are conserved components of the cytokinetic ring among Corynebacterineae that may play a critical role in the final stages of cytokinesis as they probably form a complex to promote cell separation by RipC-FtsEX. They may coordinate peptidoglycan remodeling with the biogenesis of other envelope layers during cell division [].
This family includes both microviridins and marinostatins. It seems likely that in both cases it is the C terminus which becomes the active inhibitor after post-translational modifications of the full length, pre-peptide. it is the ester linkages within the key, 12-residue. region that circularise the molecule giving it its inhibitory conformation.
This domain family is found in bacteria, and is approximately 70 amino acids in length. The family is found in association with
. There is a conserved REP sequence motif. There is a single completely conserved residue P that may be functionally important. The proteins in this family are frequently annotated as ABC Cobalt transporters however there is little accompanying literature to confirm this.
This domain is found in bacterial lipoprotein, and is approximately 140 amino acids in length. The domain is found in association with
. There is a conserved GAG sequence motif.
Nucleoside diphosphate kinases (
) (NDK) are enzymes required for the synthesis of nucleoside triphosphates (NTP) other than ATP. They provide NTPs for nucleic acid synthesis, CTP for lipid synthesis, UTP for polysaccharide synthesis and GTP for protein elongation, signal transduction and microtubule polymerisation.
NDK are proteins of 17 Kd that act via a ping-pong mechanism in which a histidine residue is phosphorylated, by transfer of the terminal phosphate group from ATP. In the presence of magnesium, the phosphoenzyme can transfer its phosphate group to any NDP, to produce an NTP.NDK isozymes have been sequenced from prokaryotic and eukaryotic sources. It has also been shown [
] that the Drosophila awd (abnormal wing discs) protein, is a microtubule-associated NDK. Mammalian NDK is also known as metastasis inhibition factor nm23. The sequence of NDK has been highly conserved through evolution. There is a single histidine residue conserved in all known NDK isozymes, which is involved in the catalytic mechanism [].The enzyme is a hexamer composed by identical subunits with a novel mononucleotide binding fold. Each subunit contains an alpha/beta domain with a four stranded, anti-parallel β-sheet [
].This alpha/beta domain is also found at the C terminus of retinitis pigmentosa 2 protein (XRP2/RP2) [
]. XRP2, a GTPase-activating protein, is required for maintenance of rod and cone photoreceptor cells in the retina [].
This entry represents HrpA, one of two related but uncharacterised DEAH-box ATP-dependent helicases in many Proteobacteria and a few high-GC Gram-positive bacteria. HrpA is about 1300 amino acids long, while its paralog HrpB, also uncharacterised, is about 800 amino acids long. Related characterised eukarotic proteins are RNA helicases associated with pre-mRNA processing. The HrpA/B homologue from Borrelia is 500 amino acids shorter but appears to be derived from HrpA rather than HrpB [
,
].
This domain is found is found towards the C terminus of proteins that contain an F-box,
, suggesting that they are effectors linked with ubiquitination.
These proteins contain a domain superfamily found in serine peptidases belonging to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin) and S53 (sedolisin), both of which are members of clan SB [
].The subtilisin family is one of the largest serine peptidase families characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence [
]. It is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses []. The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase [,
]. Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins, although the residues occur in a different order (HDS in chymotrypsin and DHS in subtilisin), but the structures show no other similarity [,
]. Some subtilisins are mosaic proteins, while others contain N- and C-terminal extensions that show no sequence similarity to any other known protein [].The proprotein-processing endopeptidases kexin, furin and related enzymes
form a distinct subfamily known as the kexin subfamily (S8B). These preferentially cleave C-terminally to paired basic amino acids. Members of this subfamily can be identified by subtly different motifs around the active site [,
]. Members of the kexin subfamily, along with endopeptidases R, T and K from the yeast Tritirachium and cuticle-degrading peptidase from Metarhizium, require thiol activation. This can be attributed to the presence of a cysteine near to the active site histidine []. Only one viral member of the subtilisin family is known, a 56kDa protease from herpes virus 1, which infects the channel catfish []. Sedolisins (serine-carboxyl peptidases) are proteolytic enzymes whose fold resembles that of subtilisin; however, they are considerably larger, with the mature catalytic domains containing approximately 375 amino acids. The defining features of these enzymes are a unique catalytic triad, Ser-Glu-Asp, as well as the presence of an aspartic acid residue in the oxyanion hole. High-resolution crystal structures have now been solved for sedolisin from Pseudomonas sp. 101, as well as for kumamolisin from a thermophilic bacterium, Bacillus sp. MN-32. Mutations in the human gene leads to a fatal neurodegenerative disease [
].
The phage-encoded excisionase protein (Xis,
) is involved in excisive recombination by regulating the assembly of the excisive intasome and by inhibiting viral integration. It adopts an unusual winged-helix structure in which two alpha helices are packed against two extended strands. Also present in the structure is a two-stranded anti-parallel β-sheet, whose strands are connected by a four-residue wing. During interaction with DNA, helix alpha2 is thought to insert into the major groove, while the wing contacts the adjacent minor groove or phosphodiester backbone. The C-terminal region of Xis is involved in interaction with phage-encoded integrase (Int), and a putative C-terminal alpha helix may fold upon interaction with Int and/or DNA [
].
Chloroperoxidase (CPO), also known as Heme haloperoxidase, is a ~250 residue heme-containing glycoprotein that is secreted by various fungi. Chloroperoxidase was first identified in Caldariomyces fumago where it catalyses the hydrogen peroxide-dependent chlorination of cyclopentanedione during the biosynthesis of the antibiotic caldarioymcin. Additionally, Heme haloperoxidase catalyses the iodination and bromination of a wide range of substrates. Besides performing H2O2-dependent halogenation reactions, the enzyme catalyses dehydrogenation reactions. Chloroperoxidase also functions as a catalase, facilitating the decomposition of hydrogen peroxide to oxygen and water. Furthermore, chloroperoxidase catalyses P450-like oxygen insertion reactions. The capability of chloroperoxidase to perform these diverse reactions makes it one of the most versatile of all known heme proteins [
,
].Despite functional similarities with other heme enzymes, chloroperoxidase folds into a novel tertiary structure dominated by eight helical segments [
]. Structurally, chloroperoxidase is unique, but it shares features with both peroxidases and P450 enzymes. As in cytochrome P450 enzymes, the proximal heme ligand is a cysteine, but similar to peroxidases, the distal side of the heme is polar. However, unlike other peroxidases, the normally conserved distal arginine is lacking and the catalytic acid base is a glutamic acid and not a histidine [].
This small family of proteins includes paralogs ChpX and ChpY in Synechococcus sp. (strain PCC 7942) (Anacystis nidulans R2) and other cyanobacteria, associated with distinct NAD(P)H dehydrogenase complexes. These proteins collectively enable light-dependent CO2 hydration and CO2 uptake; loss of both blocks growth at low CO2 concentrations.
ERp29 (
) is a ubiquitously expressed endoplasmic reticulum protein, and is involved in the processes of protein maturation and protein secretion in this organelle [
,
]. The protein exists as a homodimer, with each monomer being composed of two domains. The N-terminal domain featured in this family is organised into a thioredoxin-like fold that resembles the a domain of human protein disulphide isomerase (PDI) []. However, this domain lacks the C-X-X-C motif required for the redox function of PDI; it is therefore thought that the function of ERp29 is similar to the chaperone function of PDI []. The N-terminal domain is exclusively responsible for the homodimerisation of the protein, without covalent linkages or additional contacts with other domains [].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 photosynthetic apparatus in non-oxygenic bacteria consists of light-harvesting (LH) protein-pigment complexes LH1 and LH2, which use carotenoid and bacteriochlorophyll as primary donors [
]. LH1 acts as the energy collection hub, temporarily storing it before its transfer to the photosynthetic reaction centre (RC) []. Electrons are transferred from the primary donor via an intermediate acceptor (bacteriopheophytin) to the primary acceptor (quinine Qa), and finally to the secondary acceptor (quinone Qb), resulting in the formation of ubiquinol QbH2. RC uses the excitation energy to shuffle electrons across the membrane, transferring them via ubiquinol to the cytochrome bc1 complex in order to establish a proton gradient across the membrane, which is used by ATP synthetase to form ATP [,
,
]. The core complex is anchored in the cell membrane, consisting of one unit of RC surrounded by LH1; in some species there may be additional subunits [
]. RC consists of three subunits: L (light), M (medium), and H (heavy). SubunitsL and M provide the scaffolding for the chromophore, while subunit H contains a cytoplasmic domain [
]. In Rhodopseudomonas viridis, there is also a non-membranous tetrahaem cytochrome (4Hcyt) subunit on the periplasmic surface. This entry describes the photosynthetic reaction centre L and M subunits, and the homologous D1 (PsbA) and D2 (PsbD) photosystem II (PSII) reaction centre proteins from cyanobacteria, algae and plants. The D1 and D2 proteins only show approximately 15% sequence homology with the L and M subunits, however the conserved amino acids correspond to the binding sites of the phytochemically active cofactors. As a result, the reaction centres (RCs) of purple photosynthetic bacteria and PSII display considerable structural similarity in terms of cofactor organisation.The D1 and D2 proteins occur as a heterodimer that form the reaction core of PSII, a multisubunit protein-pigment complex containing over forty different cofactors, which are anchored in the cell membrane in cyanobacteria, and in the thylakoid membrane in algae and plants. Upon absorption of light energy, the D1/D2 heterodimer undergoes charge separation, and the electrons are transferred from the primary donor (chlorophyll a) via pheophytin to the primary acceptor quinone Qa, then to the secondary acceptor Qb, which like the bacterial system, culminates in the production of ATP. However, PSII has an additional function over the bacterial system. At the oxidising side of PSII, a redox-active residue in the D1 protein reduces P680, the oxidised tyrosine then withdrawing electrons from a manganese cluster, which in turn withdraw electrons from water, leading to the splitting of water and the formation of molecular oxygen. PSII thus provides a source of electrons that can be used by photosystem I to produce the reducing power (NADPH) required to convert CO2 to glucose [
,
].Also in this entry is the light-dependent chlorophyll f synthase (ChlF) from cyanobacteria such as Chlorogloeopsis fritschii. ChlF synthesizes chlorophyll f or chlorophyllide f, which is able to absorb far red light, probably by oxidation of chlorophyll a or chlorophyllide a and reduction of plastoquinone [
].
This domain of about 100 residues is found multiple (up to 35) copies in long proteins from several species of Vibrio, Colwellia, Bradyrhizobium, and Shewanella (hence the name VCBS) and in smaller copy numbers in proteins from several other bacteria. The large protein size and repeat copy numbers, species distribution, and suggested activities of several member proteins suggests a role for this domain in adhesion.
Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites [
,
]. About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to - the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits. Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome [
,
].Ribosomal protein L14 is one of the proteins from the large ribosomal subunit.
In eubacteria, L14 is known to bind directly to the 23S rRNA. It belongs to a family of ribosomal proteins, which have been grouped on the basis of sequence similarities. Based on amino-acid sequence homology, it is predicted that ribosomal protein L14 is a member of a recently identified family of structurally related RNA-binding proteins []. L14 is a protein of 119 to 137 amino-acid residues.
ATP-dependent DNA helicase RecG is involved in the processing of stalled replication forks. It acts by reversing the fork past the damage to create a four-way junction that allows template switching and lesion bypass [
]. RecG comprises three structural domains: N-terminal domain 1 (residues 1-350) and C-terminal domain 2 (residues 351-549) and domain3 (residues 550-780). This entry represents an antiparallel four helix bundle motif of the domain 1 [].
This entry represents bacterial phycoerythrobilin:ferredoxin oxidoreductases. They are involved in the biosynthesis of photosynthetic antennae of cyanobacteria.
This family summarizes bacterial proteins related to CpxP, a periplasmic protein that forms part of a two-component system which acts as a global modulator of cell-envelope stress in Gram-negative bacteria. CpxP aids in combating extracytoplasmic protein-mediated toxicity, and may also be involved in the response to alkaline pH [
]. Functioning as a dimer, it inhibits activation of the kinase CpxA, but also plays a vital role in the quality control system of P pili. It has been suggested that CpxP directly interacts with CpxA via its concave polar surface []. Another member of this family, Spy, is also a periplasmic protein that may be involved in the response to stress []. The homology between CpxP and Spy suggests similar functions. A characteristic 5-residue sequence motif LTXXQ is found repeated twice in many members of this family [].
This entry represents a domain superfamily found in the pretoxin HINT domain protein and the C-terminal of protein hedgehog.Hedgehog proteins are a family of secreted signal molecules required for embryonic cell differentiation. They are synthesised as inactive precursors with an N-terminal signalling domain linked to a C-terminal autoprocessing domain. The three-dimensional structure of the autoprocessing domain shows similarity with the β-strand core of intein splicing domains. It has hence been termed the Hedgehog/Intein (Hint) domain [
].
The member of this family from Haemophilus influenzae, Probable ribonuclease HepT (also known as HI0074), is an homologue of the mRNA nuclease HepT (SO_3166) from Shewanella oneidensis, being probably the toxic component of a type VII toxin-antitoxin (TA) system. It contains a HEPN (higher eukaryotes and prokaryotes nucleotide-binding) domain containing a RX4-6H motif whose conformations are remarkably different form SO_3166, indicating that they have different substrate-binding specificities [
]. It forms a complexwith HI0073 (
), encoded by the adjacent gene, which contains a nucleotidyltransferase nucleotide binding domain (
) [
].
The RimP protein (also known as YlxS in Bacillus subtilis) facilitates maturation of the 30S ribosomal subunit, and is required for the efficient production of translationally competent ribosomes [].The C-terminal domain of RimP contains a SH3-type barrel.
Iron-sulphur (FeS) clusters are important cofactors for numerous proteins involved in electron transfer, in redox and non-redox catalysis, in gene regulation, and as sensors of oxygen and iron. These functions depend on the various FeS cluster prosthetic groups, the most common being [2Fe-2S] and [4Fe-4S][
]. FeS cluster assembly is a complex process involving the mobilisation of Fe and S atoms from storage sources, their assembly into [Fe-S]form, their transport to specific cellular locations, and their transfer to recipient apoproteins. So far, three FeS assembly machineries have been identified, which are capable of synthesising all types of [Fe-S] clusters: ISC (iron-sulphur cluster), SUF (sulphur assimilation), and NIF (nitrogen fixation) systems.The ISC system is conserved in eubacteria and eukaryotes (mitochondria), and has broad specificity, targeting general FeS proteins [
,
]. It is encoded by the isc operon (iscRSUA-hscBA-fdx-iscX). IscS is a cysteine desulphurase, which obtains S from cysteine (converting it to alanine) and serves as a S donor for FeS cluster assembly. IscU and IscA act as scaffolds to accept S and Fe atoms, assembling clusters and transferring them to recipient apoproteins. HscA is a molecular chaperone and HscB is a co-chaperone. Fdx is a [2Fe-2S]-type ferredoxin. IscR is a transcription factor that regulates expression of the isc operon. IscX (also known as YfhJ) appears to interact with IscS and may function as an Fe donor during cluster assembly [
].The SUF system is an alternative pathway to the ISC system that operates under iron starvation and oxidative stress. It is found in eubacteria, archaea and eukaryotes (plastids). The SUF system is encoded by the suf operon (sufABCDSE), and the six encoded proteins are arranged into two complexes (SufSE and SufBCD) and one protein (SufA). SufS is a pyridoxal-phosphate (PLP) protein displaying cysteine desulphurase activity. SufE acts as a scaffold protein that accepts S from SufS and donates it to SufA [
]. SufC is an ATPase with an unorthodox ATP-binding cassette (ABC)-like component. SufA is homologous to IscA [], acting as a scaffold protein in which Fe and S atoms are assembled into [FeS]cluster forms, which can then easily be transferred to apoproteins targets.
In the NIF system, NifS and NifU are required for the formation of metalloclusters of nitrogenase in Azotobacter vinelandii, and other organisms, as well as in the maturation of other FeS proteins. Nitrogenase catalyses the fixation of nitrogen. It contains a complex cluster, the FeMo cofactor, which contains molybdenum, Fe and S. NifS is a cysteine desulphurase. NifU binds one Fe atom at its N-terminal, assembling an FeS cluster that is transferred to nitrogenase apoproteins [
]. Nif proteins involved in the formation of FeS clusters can also be found in organisms that do not fix nitrogen [].This entry represents the HscA chaperone protein from the SUF system. HscA (or Hsc66) is a specialised bacterial Hsp70-class molecular chaperone that participates in the assembly of iron-sulphur cluster proteins. HscA resembles DnaK, but belongs to a separate clade. HscA interacts with IscU, which is believed to serve as a template for Fe-S cluster formation. The HscA-IscU interaction is facilitated by the J-type co-chaperone protein HscB (or Hsc20), which binds to both HscA and IscU, bringing them into contact with each other. HscA recognises a conserved LPPVK sequence motif at positions 99-103 of IscU [
].
Potassium channel, voltage dependent, Kv1.4, tandem inactivation domain
Type:
Domain
Description:
Potassium channels are the most diverse group of the ion channel family [
,
]. They are important in shaping the action potential, and in neuronal excitability and plasticity []. The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groups []: the practically non-inactivating 'delayed' group and the rapidly inactivating 'transient' group.These are all highly similar proteins, with only small amino acid changes causing the diversity of the voltage-dependent gating mechanism, channel conductance and toxin binding properties. Each type of K
+channel is activated by different signals and conditions depending on their type of regulation: some open in response to depolarisation of the plasma membrane; others in response to hyperpolarisation or an increase in intracellular calcium concentration; some can be regulated by binding of a transmitter, together with intracellular kinases; while others are regulated by GTP-binding proteins or other second messengers [
]. In eukaryotic cells, K+channels are involved in neural signalling and generation of the cardiac rhythm, act as effectors in signal transduction pathways involving G protein-coupled receptors (GPCRs) and may have a role in target cell lysis by cytotoxic T-lymphocytes [
]. In prokaryotic cells, they play a role in the maintenance of ionic homeostasis [].All K
+channels discovered so far possess a core of alpha subunits, each comprising either one or two copies of a highly conserved pore loop domain (P-domain). The P-domain contains the sequence (T/SxxTxGxG), which has been termed the K
+selectivity sequence. In families that contain one P-domain, four subunits assemble to form a selective pathway for K
+across the membrane. However, it remains unclear how the 2 P-domain subunits assemble to form a selective pore. The functional diversity of these families can arise through homo- or hetero-associations of alpha subunits or association with auxiliary cytoplasmic beta subunits. K
+channel subunits containing one pore domain can be assigned into one of two superfamilies: those that possess six transmembrane (TM) domains and those that possess only two TM domains. The six TM domain superfamily can be further subdivided into conserved gene families: the voltage-gated (Kv) channels; the KCNQ channels (originally known as KvLQT channels); the EAG-like K
+channels; and three types of calcium (Ca)-activated K
+channels (BK, IK and SK) [
]. The 2TM domain family comprises inward-rectifying K+channels. In addition, there are K
+channel alpha-subunits that possess two P-domains. These are usually highly regulated K
+selective leak channels.
The Kv family can be divided into several subfamilies on the basis of sequence similarity and function. Four of these subfamilies, Kv1 (Shaker), Kv2 (Shab), Kv3 (Shaw) and Kv4 (Shal), consist of pore-forming alpha subunits that associate with different types of beta subunit. Each alpha subunit comprises six hydrophobic TM domains with a P-domain between the fifth and sixth, which partially resides in the membrane. The fourth TM domain has positively charged residues at every third residue and acts as a voltage sensor, which triggers the conformational change that opens the channel pore in response to a displacement in membrane potential []. More recently, 4 new electrically-silent alpha subunits have been cloned: Kv5 (KCNF), Kv6 (KCNG), Kv8 and Kv9 (KCNS). These subunits do not themselves possess any functional activity, but appear to form heteromeric channels with Kv2 subunits, and thus modulate Shab channel activity []. When highly expressed, they inhibit channel activity, but at lower levels show more specific modulatory actions.The first Kv1 sequence (also known as Shaker) was found in Drosophila melanogaster (Fruit fly). Several vertebrate potassium channels with similar amino acid sequences were subsequently found and, together with the D. melanogaster Shaker channel, now constitute the Kv1 family. The family consists of at least 6 genes (Kv1.1, Kv1.2, Kv1.3, Kv1.4, Kv1.5 and Kv1.6) which each play distinct physiological roles. A conserved motif found towards the C terminus of these channels is required for efficient processing and surface expression [
]. Variations in this motif account for the differences in cell surface expression and localisation between family members. These channels are mostly expressed in the brain, but can also be found in non-excitable cells, such as lymphocytes []. This entry features the tandem inactivation domain found at the N terminus of the Kv1.4 potassium channel. It is composed of two subdomains. Inactivation domain 1 (ID1, residues 1-38) consists of a flexible N terminus anchored at a 5-turn helix, and is thought to work by occluding the ion pathway, as is the case with a classical ball domain. Inactivation domain 2 (ID2, residues 40-50) is a 2.5 turn helix with a high proportion of hydrophobic residues that probably serves to attach ID1 to the cytoplasmic face of the channel. In this way, it can promote rapid access of ID1 to the receptor site in the open channel. ID1 and ID2 function together to bring about fast inactivation of the Kv1.4 channel, which is important for the role of the channel in short-term plasticity [
].
Ganglioside GM2 activator (GM2-AP) is a is a lysosomal lipid transfer protein that is essential for the hydrolytic conversion of ganglioside GM2 to GM3 by beta-hexosaminidase A [
]. The crystal structure of apo-GM2-AP consists of a novel β-cup fold with a spacious hydrophobic interior [,
].
The C-terminal domain of the enolase adopts a TIM barrel fold that contains a metal binding site [
]. Proteins containing this domain also include D-glucarate dehydratase-like proteins and some uncharacterised proteins [].
This antiparallel beta sandwich domain occurs in the C-terminal of mollusc haemocyanins, which are copper-containing oxygen carriers occurring freely dissolved in the hemolymph of many mollusks and arthropods. Each mollusc haemocyanin contains several globular oxygen binding functional units. Each unit consists of an α-helical copper binding domain (
) and an antiparallel beta sandwich domain [
,
].
This entry represents a conserved hypothetical protein about 240 residues in length found so far in Proteobacteria including Shewanella oneidensis and Ralstonia solanacearum, usually as part of a paralogous family. The function is unknown.
The 15 aa repeat is found in the APC protein family. It is involved in binding beta-catenin [
] along with the repeats. Many human cancer mutations map to the region around these motifs, and may be involved in disrupting their binding of beta-catenin.
Herpesviruses are enveloped by a lipid bilayer that contains at least a dozen glycoproteins. The virion surface glycoproteins mediate recognition of susceptible cells and promote fusion of the viral envelope with the cell membrane, leading to virus entry. No single glycoprotein associated with the virion membrane has been identified as the fusogen [
].Glycoprotein L (gL) forms a non-covalently linked heterodimer with glycoprotein H (gH). This heterodimer is essential for virus-cell and cell-cell fusion since the association of gH and gL is necessary for correct localisation of gH to the virion or cell surface. gH anchoring the heterodimer to the plasma membrane through its transmembrane domain. gL lacks a transmembrane domain and is secreted from cells when expressed in the absence of gH [
].This entry represents Herpesvirus glycoprotein L (gL), which is a virion associated envelope glycoprotein [
]. Heterodimer formation between gH and gL has been demonstrated in both virions and infected cells []. Heterodimer formation between gL and gH is important for the proper folding of gH and its insertion into the membrane because the anti-gH conformation-dependent monoclonal antibodies (mAbs) 53S and LP11 bind gH only when gL is present [,
].
This family consists of several bacterial ethanolamine ammonia-lyase small subunit (EutC) sequences. Ethanolamine ammonia-lyase is a bacterial enzyme that catalyses the adenosylcobalamin-dependent conversion of certain vicinal amino alcohols to oxo compounds and ammonia [
].
This domain of unknown function is found in viruses. Proteins in this family are typically between 145 and 1707 amino acids in length. The family is found in association with
,
,
,
,
. There is a single completely conserved residue L that may be functionally important.
Transient receptor potential cation channel subfamily V
Type:
Family
Description:
Transient receptor potential (TRP) channels can be described as tetramers formed by subunits with six transmembrane domains and containing cation-selective pores, which in several cases show high calcium permeability. The molecular architecture of TRP channels is reminiscent of voltage-gated channels and comprises six putative transmembrane segments (S1-S6), intracellular N- and C-termini, and a pore-forming reentrant loop between S5 and S6 [
].TRP channels represent a superfamily conserved from worms to humans that comprise seven subfamilies [
]: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin or long TRPs), TRPA (ankyrin, whose only member is Transient receptor potential cation channel subfamily A member 1, TrpA1), TRPP (polycystin), TRPML (mucolipin) and TRPN (Nomp-C homologues), which has a single member that can be found in worms, flies, and zebrafish. TRPs are classified essentially according to their primary amino acid sequence rather than selectivity or ligand affinity, due to their heterogeneous properties and complex regulation.TRP channels are involved in many physiological functions, ranging from pure sensory functions, such as pheromone signalling, taste transduction, nociception, and temperature sensation, over homeostatic functions, such as Ca2+ and Mg2+ reabsorption and osmoregulation, to many other motile functions, such as muscle contraction and vaso-motor control [
].The TRPV (vanilloid) subfamily can be divided into two distinct groups. The first, which comprises TrpV1, TrpV2, TrpV3, and TrpV4, with nonselective cation conducting pores, has members which can be activated by temperature as well as chemical stimuli. They are involved in a range of functions including nociception, thermosensing and osmolarity sensing. The second group, which consists of TrpV5 and TrpV6, (also known as epithelial calcium channels 1 and 2), highly calcium selective, are involved in renal Ca2+ absorption/reabsorption [
,
].
Transient receptor potential cation channel subfamily V member 5/6
Type:
Family
Description:
Transient receptor potential (TRP) channels can be described as tetramers formed by subunits with six transmembrane domains and containing cation-selective pores, which in several cases show high calcium permeability. The molecular architecture of TRP channels is reminiscent of voltage-gated channels and comprises six putative transmembrane segments (S1-S6), intracellular N- and C-termini, and a pore-forming reentrant loop between S5 and S6 [
].TRP channels represent a superfamily conserved from worms to humans that comprise seven subfamilies [
]: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin or long TRPs), TRPA (ankyrin, whose only member is Transient receptor potential cation channel subfamily A member 1, TrpA1), TRPP (polycystin), TRPML (mucolipin) and TRPN (Nomp-C homologues), which has a single member that can be found in worms, flies, and zebrafish. TRPs are classified essentially according to their primary amino acid sequence rather than selectivity or ligand affinity, due to their heterogeneous properties and complex regulation.TRP channels are involved in many physiological functions, ranging from pure sensory functions, such as pheromone signalling, taste transduction, nociception, and temperature sensation, over homeostatic functions, such as Ca2+ and Mg2+ reabsorption and osmoregulation, to many other motile functions, such as muscle contraction and vaso-motor control [
].The TRPV (vanilloid) subfamily can be divided into two distinct groups. The first, which comprises TrpV1, TrpV2, TrpV3, and TrpV4, with nonselective cation conducting pores, has members which can be activated by temperature as well as chemical stimuli. They are involved in a range of functions including nociception, thermosensing and osmolarity sensing. The second group, which consists of TrpV5 and TrpV6, (also known as epithelial calcium channels 1 and 2), highly calcium selective, are involved in renal Ca2+ absorption/reabsorption [
,
].This entry represetns the TRPV5/6 group of channels.
Transient receptor potential cation channel subfamily V member 1-4
Type:
Family
Description:
Transient receptor potential (TRP) channels can be described as tetramers formed by subunits with six transmembrane domains and containing cation-selective pores, which in several cases show high calcium permeability. The molecular architecture of TRP channels is reminiscent of voltage-gated channels and comprises six putative transmembrane segments (S1-S6), intracellular N- and C-termini, and a pore-forming reentrant loop between S5 and S6 [
].TRP channels represent a superfamily conserved from worms to humans that comprise seven subfamilies [
]: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin or long TRPs), TRPA (ankyrin, whose only member is Transient receptor potential cation channel subfamily A member 1, TrpA1), TRPP (polycystin), TRPML (mucolipin) and TRPN (Nomp-C homologues), which has a single member that can be found in worms, flies, and zebrafish. TRPs are classified essentially according to their primary amino acid sequence rather than selectivity or ligand affinity, due to their heterogeneous properties and complex regulation.TRP channels are involved in many physiological functions, ranging from pure sensory functions, such as pheromone signalling, taste transduction, nociception, and temperature sensation, over homeostatic functions, such as Ca2+ and Mg2+ reabsorption and osmoregulation, to many other motile functions, such as muscle contraction and vaso-motor control [
].The TRPV (vanilloid) subfamily can be divided into two distinct groups. The first, which comprises TrpV1, TrpV2, TrpV3, and TrpV4, with nonselective cation conducting pores, has members which can be activated by temperature as well as chemical stimuli. They are involved in a range of functions including nociception, thermosensing and osmolarity sensing. The second group, which consists of TrpV5 and TrpV6, (also known as epithelial calcium channels 1 and 2), highly calcium selective, are involved in renal Ca2+ absorption/reabsorption [
,
].This entry represents the TRPV1-4 group of channels. Members of this family are found in chordates.
This domain family is found in bacteria and eukaryotes, and is approximately 80 amino acids in length. There is a single completely conserved residue E that may be functionally important.
Prepilin peptidase dependent protein C-like, C-terminal domain
Type:
Domain
Description:
This entry represents a domain found al proteins mainly found in Enterobacterales, including Prepilin peptidase-dependent protein C from Escherichia coli (PpdC). PpdC is predicted to be a bitopic inner membrane protein. This domain is found in association with
. There are two completely conserved C residues that may be functionally important.
The mouse four-jointed box protein 1 (fjx1) gene and Drosophila four-jointed (fj) gene are homologues [
,
,
,
]. Fj encodes a partially secreted transmembrane (TM) type II glyco- protein. In Drosophila, the gene is a downstream target of the Notch signalling pathway in leg-segmentation and planar-cell polarity processes during eye development. Conserved in vertebrates, the murine homologue, fjx1, is also a direct target of Notch signalling [
]. The gene is expressed in mouse brain, in the peripheral nervous system, in epithelial cells of multiple organs, and during limb development [].The protein product is processed and secreted as a presumptive ligand [
]. fjx1 binding sites have been identified at complementary locations, suggesting that fjx1 may function as a novel signalling molecule [].
This entry represent the N-terminal domain of the proteins EssC from Firmicutes. EssC contains the FtsK domains and is typically between 107 and 121 amino acids in length. It is required for secretion of EsxA and EsxB. It is related to the FtsK/SpoIIIE proteins (
), which are DNA transporters responsible for translocating missegregated chromosomes after the completion of cell division [
].
This domain family is found in bacteria and eukaryotes, and is typically between 180 and 198 amino acids in length. There is a conserved DQP sequence motif.
FAM20 is a family of secreted proteins with a potential role in regulating differentiation and function of hematopoietic and other tissues. Proteins in this family include FAM20A [
], FAM20B or glycosaminoglycan xylosylkinase [], and FAM20C or dentin matrix protein 4 [,
].
Sequences found in this entry are derived from a number of bacteriophage and prophage proteins. They are similar to gp58 (
), a minor structural protein of Lactococcus delbrueckii bacteriophage LL-H [
].
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [
,
]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits [
]. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.This entry represents the tail domain of the integrin beta subunit. It forms a four-stranded β-sheet that contains parallel and antiparallel strands and faces an alpha helix found at the N terminus of this domain [
]. Interactions between the α-helix and the β-sheet are mostly hydrophobic and involve a disulphide bond. The rear of the beta sheet is covered with a long A-B loop.
This short domain is found at the C terminus of vascular endothelial growth factor (VEGF). It has been shown to have heparin binding activity [
].Proteins containing this domain include VEGF-A, which is a growth factor active in angiogenesis, vasculogenesis and endothelial cell growth [
]. VEGF-A also promotes a wide range of neuronal functions, including neurogenesis, neuronal migration, neuronal survival and axon guidance [].
