This family consists of various bacterial plasmid replication (Rep) proteins. Rep is a rolling-circle replication (RCR) initiation protein and provides endonuclease activity. It is generally found as hexamer, in contrast to other RCR proteins that are purified as monomers or dimers.These proteins are essential for replication of plasmids, the Rep proteins are topoisomerases that nick the positive stand at the plus origin of replication and also at the single-strand conversion sequence [
]. Crystal structure of RepB revealed that the DNA-binding capability as well as the nuclease and strand-transfer activities reside in its N-terminal origin binding domain (OBD), which belongs to the replication (Rep) class of the HUH endonuclease superfamily. The C-terminal oligomerization domains of the protein form a rigid cylindrical scaffold to which the N-terminal DNA-binding/catalytic domains are attached as highly flexible appendages, featuring multiple orientations [].
Proteins in this entry contain an ATP/GTP binding P-loop motif. They are found
associated with IS21 family insertion sequences []. Functionally they have not been characterised, but they may be involved in transposition [].
Birnavirus VP3 is involved in virus morphogenesis. It interacts with the structural protein VP2, with the double-stranded RNA genome, and with the virus-encoded, RNA-dependent RNA polymerase (RdRP), VP1, playing a role in both viral capsid formation, recruitment of VP1 into the capsid and encapsidation of the viral genome [
].
This is a group of animal proteins which share the same overall structure, including ZBED5/8, EPM2A-interacting protein 1 and FAM200A/B. EPM2A-interacting protein 1 interacts with laforin, the product of the EPM2A gene, which is mutated in an autosomal recessive form of adolescent progressive myoclonus epilepsy [
].
This family consists of various proteins from the Herpesviridae that are similar to Human herpesvirus 1 (HHV-1) UL6 virion protein. UL6 is essential for cleavage and packaging of the viral genome [
]. UL6 forms the DNA entry portal; it exists at a unique site in the capsid and forms a channel for entry of DNA into the capsid [].
Infectious pancreatic necrosis virus (IPNV), a birnavirus, is an important pathogen in fish farms. Analyses of viral proteins showed that VP2 is the major structural and immunogenic polypeptide of the virus [
,
]. All neutralizing monoclonal antibodies are specific to VP2 and bind to continuous or discontinuous epitopes. The variable domain of VP2 and the 20 adjacent amino acids of the conserved C-terminal are probably the most important in inducing an immune response for the protection of animals [].The large RNA segment of the Birnaviridae codes for a polyprotein (N-VP2-VP4-VP3-C), most of which is then processed to generate the constituent polypeptides. VP4 protein is involved in generating VP2 and VP3 [
]. Recombinant VP3 is more immunogenic than recombinant VP2 [].
Human immunodeficiency virus (HIV) is the human retrovirus associated with AIDS (acquired immune deficiency syndrome), and SIV its simian counterpart. Three main groups of primate lentivirus are known, designated Human immunodeficiency virus 1 (HIV-1), Human immunodeficiency virus 2 (HIV-2)/Simian immunodeficiency virus - mac (SIVMAC)/Simian immunodeficiency virus - sm (SIVSM) and Simian immunodeficiency virus - agm (SIVAGM). Simian immunodeficiency virus - mnd (SIVMND) has been suggested to represent a fourth distinct group [
]. These groups are believed to have diverged from a common ancestor long before the spread of AIDS in humans. Genetic variation in HIV-1 and HIV-2 has been studied extensively, and the nucleotide sequences reported for several strains [].ORF analysis has revealed two open reading frames, yielding the so-called R- and X-ORF proteins, which show a high degree of sequence similarity.Vpx plays a role in nuclear translocation of the viral pre-integration complex (PIC) and is thus required for the virus to infect non-dividing cells. Vpr also plays a role in nuclear translocation of the (PIC) and may target specific host proteins for degradation by the 26S proteasome. It acts by associating with the cellular CUL4A-DDB1 E3 ligase complex through direct interaction with host VPRPB/DCAF-1. This would result in cell cycle arrest or apoptosis in infected cells, creating a favourable environment for maximizing viral expression and production by rendering the HIV-1 LTR transcription more active.
Complex IV (CIV) is a copper-heme oxidase that couples electron transfer from cytochrome c to oxygen with proton extrusion across the inner membrane to contribute to the proton gradient required for ATP generation. Human CIV is formed by three catalytic core subunits (COX1/2/3). TMEM177 is a mitochondrial protein involved in the COX2 biogenesis pathway [
].
Mucin-like protein 3 (MUCL3; also known as diffuse panbronchiolitis critical region protein 1) is a single-pass type I membrane protein of unknown function. It is expressed in numerous tissues, with most-abundant expression in lung, kidney, and testis [
].
This family consists of matrix-remodeling-associated protein 7 (also known as transmembrane anchor protein 1). It is a single-pass membrane protein with unknown function.
This family consist of coat proteins from closterovirus, which belong to the Closteroviridae, which have a positive strand ssRNA genome with no DNA stage during replication. The viral coat protein encapsulates and protects the viral genome. Both the large cp1 and smaller cp2 coat protein originate from the same primary transcript [
]. Members of the Closterovirus include Beet yellows virus (BYV) (Sugar beet yellows virus) and Grapevine leafroll-associated virus 7.
Potexviruses and Carlaviruses are plant-infecting viruses whose genome consist of a single-stranded RNA molecule encapsided in a coat protein. The genome of many Potexviruses is known and their coat protein sequence has been shown to be rather well conserved [
]. The same observation applies to the coat protein of a variety of Carlaviruses whose sequences are related to those of Potexviruses [,
]. The coat proteins of Potexviruses and of Carlavirusescontain from 190 to 300 amino acid residues. The best conserved region of these coat proteins is located in the central part.
A number of bacterial and plant toxins act by inhibiting protein synthesis in eukaryotic cells. The toxins of the shiga and ricin family inactivate 60S ribosomal subunits by an N-glycosidic cleavage which releases a specific adenine base from the sugar-phosphate backbone of 28S rRNA [
,
,
]. Members of the family include shiga and shiga-like toxins, and type I (e.g. trichosanthin and luffin) and type II (e.g. ricin, agglutinin and abrin) ribosome inactivating proteins (RIPs). All these toxins are structurally related. RIPs have been of considerable interest because of their potential use, conjugated with monoclonal antibodies, as immunotoxins to treat cancers. Further, trichosanthin has been shown to have potent activity against HIV-1-infected T cells and macrophages []. Elucidation of the structure-function relationships of RIPs has therefore become a major research effort. It is now known that RIPs are structurally related. A conserved glutamic residue has been implicated in the catalytic mechanism []; this lies near a conserved arginine, which also plays a role in catalysis [].
Cyclin-D1-binding protein 1 (CCNDBP1, also known as GCIP) is a helix-loop-helix protein that may negatively regulate cell cycle progression and could function in tumour suppression [
]. It may act, at least in part, via inhibition of the cyclin-D1/CDK4 complex, thereby preventing phosphorylation of RB1 and blocking E2F-dependent transcription [,
].
The filoviridae are a group of viruses that cause haemorrhagic fevers with
a high mortality rate. The family currently contains three viruses: Ebola virus sp., Lake Victoria marburgvirus and Reston ebolavirus, named after their corresponding outbreak regions. They possess negative-stranded RNA genomes, which encode at least 7 proteins. The VP35 protein is found in the genomes of all filoviruses. Its function is presently unknown, but it is thought to share the function of the phosphorylated proteins (polymerase subunits) of rhabdoviruses and paramyxoviruses due to its position in the genome. There is no evidence however, to suggest that VP35 is phosphorylated [].
Tau proteins are microtubule-associated proteins that are involved in
microtubule assembly and stabilisation. They may also play a wider role in cellular shape, motility and signal transduction []. Tau mRNA is expressed predominantlyin neurones, and particularly in their axons. Quite a number of isoforms
have been detected, which in human brain have been shown to arise fromalternative splicing of an mRNA from a single gene located on chromosome 17.
The isoforms contain 352-441 amino acid residues. A larger tau isoform hasalso been detected, which is expressed principally in the peripheral nervous
system [].Each isoform contains a variable number of C-terminal repeat
regions that are thought to be responsible for tubulin-binding. The acidic N-terminal region projects from the micro-tubule surface when Tau is bound and may interact with other cytoskeletal elements. The middle region is proline-rich and may be a further binding site. It contains the target sites of many kinases, phosphorylation of this region may result in a change in the conformational state of the protein, and affect its ability to bind microtubules [].Tau does not appear to be an essential protein, since transgenic micelacking tau appear to develop a normal nervous system with only mild
alterations in the structure of certain small-calibre axons []. However,it has received much recent attention due to its possible role in the
aetiogenesis of a number of human neurodegenerative diseases, filamentousinclusions containing tau having been found in the brains of patients
diagnosed with Alzheimer's disease, Pick's disease and progressivesupranuclear palsy. Furthermore, tau gene mutations have been found in
patients suffering familial frontotemporal dementia, which result inabnormal tau protein aggregates forming in the brain tissue [
].
This entry includes a group of plant transcriptional repressors, known as Ovate proteins. In Arabidopsis, there are 18 Ovate family members [
]. They function as transcriptional repressors that regulate growth and development in plants [,
,
].
Bleomycin (Blm) is a glycopeptide antibiotic produced naturally by actinomycetes. It is a strong DNA-cutting agent and thus finds use as
a potent anti-cancer drug. The DNA-cutting mechanism is complex, involving concomitant oxidation of FeII and reduction of oxygen. In
addition to iron, Blm binds other transition metals: cobalt, nickel, copper and zinc. Actinomycetes have developed a defence mechanism
against this lethal compound, producing a protein that confers resistance to Blm through drug sequestering.
The crystal structure of the bleomycin resistance protein reveals 2identically-folded halves, each having an alpha/beta fold but showing no
sequence similarity []. Each half comprises a 4-stranded β-sheet anda short α-helix (3 turns). The sheets within each half lie roughly at
right-angles and are related by an approximate 2-fold axis. The crystalpacking shows compact dimers that have a hydrophobic interface and are
involved in mutual chain exchange.
This entry represents a group of proteins including proline-rich protein 29 (PRR29) and the uncharacterised protein C21orf58. The function of this family is unknown.
14-3-3 protein sigma isoform, also known as stratifin or human mammary epithelial marker (HME) 1, has been most directly linked to tumour development [
,
]. In humans, it is expressed by the SFN gene, strictly in stratified squamous epithelial cells in response to DNA damage where it is transcriptionally induced in a p53-dependent manner, subsequently causing cell-cycle arrest at the G2/M checkpoint []. Up-regulation and down-regulation of 14-3-3 sigma expression have both been described in tumours. For example, in human breast cancer, 14-3-3 sigma is predominantly down-regulated by CpG methylation, acting as both a tumour suppressor and a prognostic indicator [], while in human scirrhous-type gastric carcinoma (SGC), it is up-regulated and may play an important role in SGC carcinogenesis and progression []. Loss of 14-3-3 sigma expression sensitizes tumour cells to treatment with conventional cytostatic drugs, making this protein an attractive therapeutic target [].
This entry represents a group of proline-rich fungal proteins, including Hua1 from budding yeasts and SPAC17A5.10 from fission yeasts. Hua1 is predicted to be involved in assembly and disassembly of the actin cytoskeleton [
].
The lipocalins are a diverse, interesting, yet poorly understood family of
proteins composed, in the main, of extracellular ligand-binding proteinsdisplaying high specificity for small hydrophobic molecules [
,
]. Functionsof these proteins include transport of nutrients, control of cell regulation, pheromone transport, cryptic colouration and the enzymatic synthesis
of prostaglandins.The crystal structures of several lipocalins have been solved and show a novel 8-stranded anti-parallel β-barrel fold well conserved within the
family. Sequence similarity within the family is at a much lower level andwould seem to be restricted to conserved disulphides and 3 motifs, which
form a juxtaposed cluster that may act as a common cell surface receptorsite [
]. By contrast, at the more variable end of the fold are found an internal ligand binding site and a putative surface for the formation of
macromolecular complexes []. The anti-parallel β-barrel fold is alsoexploited by the fatty acid-binding proteins (which function similarly by
binding small hydrophobic molecules), by avidin and the closely relatedmetalloprotease inhibitors, and by triabin. Similarity at the sequence
level, however, is less obvious, being confined to a single short N-terminal motif.
The lipocalin family can be subdivided into kernal and outlier sets. Thekernal lipocalins form the largest self-consistent group, comprising the subfamily of tick histamine-binding proteins. The outlier lipocalins form several smaller distinct subgroups:
the OBPs, the von Ebner's gland proteins, alpha-1-acid glycoproteins, tick histamine binding proteins and the nitrophorins.
The tick histamine binding proteins are the most recently identified set of
outlier lipocalins. The structure of one tick histamine binding protein hasbeen solved [
] and has shown the proteins to have the characteristic lipocalin fold but without any appreciable sequence similarity. The tick
histamine binding proteins are secreted into the saliva of the ixodid tick Rhipicephalus appendiculatus and share functional similarity with the
nitrophorins, sequestering histamine at the wound site. Because the tickhistamine binding proteins outcompete histamine receptors, they are able to
overcome host inflammatory and immune responses. This enables the ticks tofeed for extended periods, lasting from days to several weeks, and are able
to gorge themselves on large blood meals increasing their body mass 100 fold.Unlike nitrophorins, the tick proteins do not bind haem (or other cofactor),
but ligate histamine directly in two rigid orthogonally-arranged binding sites, at opposing ends of the lipocalin anti-parallel β-barrel, which
have an unusually polar character.
Bicarbonate (HCO
3-) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested four different HCO
3-transport modes. Anion exchanger proteins exchange HCO
3-for Cl
-in a reversible, electroneutral manner [
]. Na+/HCO
3-co-transport proteins mediate the coupled movement of Na
+and HCO
3-across plasma membranes, often in an electrogenic manner [
]. Na+driven Cl
-/HCO
3-exchange and K
+/HCO
3-exchange activities have also been detected in certain cell types, although the molecular identities of the proteins responsible remain to be determined.
Sequence analysis of the two families of HCO
3-transporters that have been cloned to date (the anion exchangers and Na
+/HCO
3-co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO
3-and are inhibited by a class of pharmacological agents called disulphonic stilbenes [
]. They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.Anion exchange proteins participate in pH and cell volume
regulation. They are glycosylated, plasma-membrane transport proteins thatexchange hydrogen carbonate (HCO
3-) for chloride (Cl
-) in a reversible,
electroneutral manner [,
]. To date three anion exchanger isoforms havebeen identified (AE1-3), AE1 being the previously-characterised erythrocyte
band 3 protein. They share a predicted topology of 12-14 transmembrane (TM)domains, but have differing distribution patterns and cellular localisation.
The best characterised isoform, AE1, is known to be the most abundantmembrane protein in mature erythrocytes. It has a molecular mass of ~95kDa
and consists of two major domains. The N-terminal 390 residues form a water-soluble, highly elongated domain that serves as an attachment site for the
binding of the membrane skeleton and other cytoplasmic proteins. Theremainder of the protein is a 55kDa hydrophobic domain that is responsible
for catalysing anion exchange. The function of the analogous domains of AE2and AE3 remains to be determined [
].Naturally-occurring mutations have been characterised in the AE1 gene, which
give rise to forms of several human diseases: included are spherocytosis,affecting red blood cells, and familial distal renal tubular acidosis, a
kidney disease associated with the formation of kidney stones [].
This entry represents the transmembrane channel-like (TMC) protein family. TMC proteins are thought to have important cellular roles, and may be modifiers of ion channels or transporters [
]. Mutations in these genes are implicated in a number of human conditions, such as deafness and epidermodysplasia verruciformis [].
The crystal proteins of Bacillus thuringiensis have been extensively studied because of their pesticidal properties and their high natural levels of production [
]. When an insect ingests these proteins, they are activated by proteolytic cleavage. The N terminus is cleaved in all of the proteins and a C-terminal extension is cleaved in some members. Once activated, the endotoxin binds to the gut epithelium and causes cell lysis by the formation of cation-selective channels, which leads to death. The activated region of the toxin is composed of three distinct structural domains: an N-terminal helical bundle domain () involved in membrane insertion and pore formation; a β-sheet central domain involved in receptor binding; and a C-terminal β-sandwich domain (
) that interacts with the N-terminal domain to form a channel [
,
].
Members of this superfamily consist of a β-sheet region followed by an α-helix and an unstructured C terminus. The β-sheet region contains a CXCX...XCXC sequence with Cys residues located in two proximal loops and pointing towards each other. This precise function of this set of bacterial proteins is, as yet, unknown [
].
This family of proteins are functionally uncharacterised. However, it is found in an O-antigen gene cluster in Escherichia coli [
] and other bacteria [] suggesting a role in O-antigen production. It has been suggested that wbnG may code for a glycine transferase [].
Noncompact myelin-associated protein, also known as MP11, plays a role in myelin formation. It is a membrane protein that inhibits myelination when it is either over- or underexpressed. MP11 expression is restricted to the placenta and peripheral nervous system, where it is expressed by Schwann cells and localized to paranodes and Schmidt-Lanterman incisures (SLIs) of non-compact myelin. [
].
This entry represents capsid vertex proteins from Myoviridae, including Gp24 from bacteriophage T4. Gp24 can self-associate to form pentons, building the capsid in association with hexamers of the major capsid protein and one dodecamer of the portal protein [
].
Members of this superfamily are found in hypothetical proteins synthesised by the archaean Sulfolobus. Their exact function has not, as yet, been determined.
This entry includes a group of fungi mitochondrial proteins, including Pet20, Sue1 and Mrx6 (YNL295W) from budding yeasts. This entry also includes Cox24 from fission yeasts.Pet20 is a mitochondrial protein which is thought to play a role in the correct assembly/maintenance of mitochondrial components [
]. Sue1 is required for degradation of unstable forms of cytochrome c []. Cox24 is a mitochondrial protein required for processing of the Cox1 transcript [].
Members of this family may be involved in the activation of nickel-pincer cofactor-dependent enzymes. LarC from Lactobacillus plantarum is involved, together with LarB and LarE, in the synthesis of the enzyme-bound cofactor of lactate racemase (LarA). Larc C binds Ni2+, and functions in nickel delivery to pyridinium-3,5-bisthiocarboxylic acid mononucleotide (P2TMN), to form the mature cofactor [
,
].
HIV protein p6 contains two late-budding domains (L domains) which are short sequence motifs essential for viral particle release. p6 interacts with the endosomal sorting complex and represents a docking site for several cellular and binding factors [
]. The PTAP motif interacts with the cellular budding factor TSG101 []. This domain is also found in some chimpanzee immunodeficiency virus (SIV-cpz) proteins.
This family represents a group on uncharacterised bacterial proteins, including YbaP from E.coli and Shigella flexneri and TP_0675 from Treponema pallidum.
In mice, 4930451I11Rik encodes two isoforms: a transmembrane (TM) form and a secreted form. FIMP is the TM form. It is a sperm-specific transmembrane protein that is essential for the sperm-oocyte fusion process [
].
Transmembrane protein 139 (TMEM139) interacts with kAE1 (the human kidney isoform of anion exchanger 1) and promotes its intracellular trafficking [
].
This family includes BREX protein BrxB from Bacillus cereus, which is part of a type 1 BREX (bacteriophage exclusion) system, a system that provides immunity against bacteriophage, which allows phage adsorption but prevents phage DNA replication, without degradation of the phage DNA [
]. The exact function of BrxB is not clear.
A number of serum transport proteins are known to be evolutionarily related,
including albumin, alpha-fetoprotein, vitamin D-binding protein and afamin[
,
,
]. Albumin is the main protein of plasma; it binds water, cations (suchas Ca
2+, Na
+and K
+), fatty acids, hormones, bilirubin and drugs - its main
function is to regulate the colloidal osmotic pressure of blood. Alphafeto-protein (alpha-fetoglobulin) is a foetal plasma protein that binds various
cations, fatty acids and bilirubin. The biological role of afamin (alpha-albumin) has not yet been characterised.
Vitamin D-binding protein (DBP) is an abundant serum glycoprotein secretedby the liver; the protein transports vitamin D sterols, binds to actin, and
is found on the surface of B-lymphocytes and subpopulations of T-lymphocytes[
]. The full length DBP contains 476-amino acids, including a 16-aminoacid signal sequence. Sequence analysis reveals 23% similarity to albumin
and to alpha-fetoprotein []. DBP contains a characteristic placement ofcysteine residues, identical to that in albumin, suggesting a similar
folding structure. Albumin and alpha-fetoprotein contain three internallyrepeated domains [
]. DBP shows similarity to the first two domains andhas a truncated third domain, supporting the view that DBP is a member of
the albumin/alpha-fetoprotein multigene family []. Within the sequence, regularly-spaced disulphide bridges generate a 3-domain
folding structure, each domain containing ~170 amino acids, with 5 or 6internal disulphide bonds, as shown schematically below:
+---+ +----+ +-----+
| | | | | |xxCxxxxxxxxxxxxxxxxCCxxCxxxxCxxxxxCCxxxCxxxxxxxxxCxxxxxxxxxxxxxxCCxxxxCxxxx
| | | | | |+-----------------+ +-----+ +---------------+
Adeno-associated virus (AAV) Replication (Rep) protein is essential for viral replication and integration. The catalytic domain has DNA binding and endonuclease activity.
Odontogenic ameloblast-associated protein, also known as apin, is a tooth-associated epithelia protein that probably plays a role in odontogenesis, the complex process that results in the initiation and generation of the tooth. It may be incorporated in the enamel matrix at the end of mineralisation process [
,
].
RHL1 is a component of the plant DNA topoisomerase VI complex. It is thought not to be involved in catalysis by topo VI, but in its regulation. RHL1 plays a role in the endoreduplication cycle, whereby cells amplify the genome without cell division. RHL1 has DNA-binding activity [
].
Cucumoviruses are tripartite RNA plant viruses believed to share a close
evolutionary relationship with Brome mosaic virus (BMV). The cucumoviruses include: Cucumber mosaic virus [], Peanut stunt virus [
] and Tomato aspermy virus []. The viral coat proteins show a high degree of sequencesimilarity [
].
The Rap1 subgroup is part of the Rap subfamily of the Ras family. It can be further divided into the Rap1a and Rap1b isoforms. In humans, Rap1a and Rap1b share 95% sequence homology, but are products of two different genes located on chromosomes 1 and 12, respectively. Rap1a is sometimes called smg p21 or Krev1 in the older literature.Rap1 proteins are believed to perform different cellular functions, depending on the isoform, its subcellular localization, and the effector proteins it binds. For example, in rat salivary gland, neutrophils, and platelets, Rap1 localizes to secretory granules and is believed to regulate exocytosis or the formation of secretory granules [
,
]. High expression of Rap1 has been observed in the nucleus of human oropharyngeal squamous cell carcinomas (SCCs) and cell lines; interestingly, in the SCCs, the active GTP-bound form localized to the nucleus, while the inactive GDP-bound form localized to the cytoplasm []. Rap1a, which is stimulated by T-cell receptor (TCR) activation, is a positive regulator of T cells by directing integrin activation and augmenting lymphocyte responses []. In murine hippocampal neurons, Rap1b determines which neurite will become the axon and directs the recruitment of Cdc42, which is required for formation of dendrites and axons []. In murine platelets, Rap1b is required for normal homeostasis in vivo and is involved in integrin activation [].
The cotJ operon proteins affect spore coat composition, and is controlled by sigma E. The genes, which include CotJB, are either required for the normal formation of the inner layers of the coat or are themselves structural components of the coat [
]. CotJB has been identified as a spore coat protein [].
This group represents protein kinase C (KPC), including zeta/iota types from mammals, protein kinase C-like 3 from round worms [
] and atypical protein kinase C (aPKC) from fruit flies []. Protein kinase C iota type (PRKCI) is a calcium- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway [
,
,
]. It is an indirect co-regulator of the stress-activated transcription factor HSF1 and the heat shock response []. It has been linked to cancers [,
].Protein kinase C zeta type is a calcium- and diacylglycerol-independent serine/threonine-protein kinase that functions in phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein (MAP) kinase cascade, and is involved in NF-kappa-B activation, mitogenic signaling, cell proliferation, cell polarity, inflammatory response and maintenance of long-term potentiation (LTP) [
].
This entry includes proteins with a structural fold similar to ribosomal protein L30e [
], and includes the bacterial proteins YlxQ from Bacillus subtilis[
], L30e from archaean 50S ribosomes and L30 from eukaryote 60S ribosomes.
The Hepatitis B virus (HBV) X gene shares sequences with both the polymerase and precore genes, carries several regulatory signals critical to the replicative cycle, and its product has a transactivating function [
]. The transactivating function is probably associated with a tumourigenic potential of HBx, since x gene sequences, encoding functional HBx, have been repeatedly found integrated into the genome of liver carcinoma cells [].
This entry includes a group of plant proteins, including CLAVATA3/ESR (CLE)-related protein 45 (CLE45) from Arabidopsis. CLE45 may be a suppressor of plant stem cell differentiation [
]. CLE45 is part of the CLE peptide family. The CLE peptide family members are small proteins that contain a signal
peptide at their N-termini and conserved CLE domain(s) at their C-termini. The signal peptide is essential for secretion of the CLE peptide into the apoplastic space where it functions non-cell autonomously. They have a varietyof functions, from embryo and endosperm development to meristem maintenance, from vascular development to autoregulation of nodulation (AON) [
].
METTL22 is a N-lysine methyltransferase that methylates Kin17, a DNA/RNA-binding protein with reported roles in DNA repair and replication and mRNA processing [].
This family seems to be restricted to mammals. It includes uncharacterized protein CXorf66, also known as secreted glycoprotein in chromosome X (SGPX). This ORF is present in chromosome X and is up-regulated in some cancers [
].
This entry consists of a group of proteins predominantly found in Firmicutes, including Uncharacterized protein YfhH from Bacillus subtilis and protein GK0453 from Geobacillus kaustophilus. GK0453 shows two small domains: an helix-turn-helix like motif is found in its N-terminal domain while an SH3-like β-barrel like structure is observed its C-terminal region. Its specific function is unknown [
]. Some of the members of this protein family are annotated as being transcriptional regulators (see
,
).
This protein family includes Spore protein YabP of the bacterial sporulation program, as found in Bacillus subtilis, Clostridium tetani, and other spore-forming members of the Firmicutes. In B. subtilis, a YabP single mutant appears to sporulate and germinate normally [
], but is in an operon with YabQ (essential for formation of the spore cortex), it near-universal among endospore-forming bacteria, and is found nowhere else. YabP is involved in spore coat assembly during the process of sporulation []. The structure of a fragment of the Spore protein YabP from Desulfitobacterium hafniense has been resolved using NMR spectroscopy, showing a homodimer with two monomeric subunits, each consisting of five anti-parallel beta strands [
].
Members of this protein family are the YabP and YqfC proteins of the bacterial sporulation program, as found in Bacillus subtilis, Clostridium tetani, and other spore-forming members of the Firmicutes. The structure of a fragment of the Spore protein YabP from Desulfitobacterium hafniense has been resolved using NMR spectroscopy, showing a homodimer with two monomeric subunits, each consisting of five anti-parallel beta strands [
].
The flgH, flgI and fliF genes of Salmonella typhimurium encode the major proteins for the L, P and M rings of the flagellar basal body [
]. In fact, the basal body consists of four rings (L,P,S and M) surrounding the flagellar rod, which is believed to transmit motor rotation to the filament []. The M ring is integral to the inner membrane of the cell, and may be connected to the rod via the S (supramembrane) ring, which lies just distal to it. The L and P rings reside in the outer membrane and periplasmic space, respectively. FlgH and FlgI, which are exported across the cell membrane to their destinations in the outer membrane and periplasmic space, have typical N-terminal cleaved signal-peptide sequences. FlgH is predicted to have an extensive β-sheet structure, in keeping with other outer membrane proteins [
].
This signature is found in coat proteins from the related tymoviruses. The coat protein is also known as the virion
protein. The virus coat is composed of 180 copies of the coat protein arranged in an icosahedral shell.
This family of fungal proteins represents the eisosome 1 family. Eisosome protein 1 is required for normal formation of eisosomes, large cytoplasmic protein assemblies that localize to specialised domains on plasma membrane and mark the site of endocytosis [
].
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 basic protein (MBP) [,
] is a hydrophilic protein that may function to maintain the correct structure of myelin, interacting with the lipids in the myelin membrane by electrostatic and hydrophobic interactions. In mammals various forms of MBP exist which are produced by the alternative splicing of a single gene; these forms differ by the presence or the absence of short (10 to 20 residues) peptides in various internal locations in the sequence. The major form of MBP is generally a protein of about 18.5 Kd (170 residues). MBP is the target of many post-translational modifications: it is N-terminally acetylated, methylated on an arginine residue, phosphorylated by various serine/threonine protein-kinases, and deamidated on some glutamine residues.
Neuronal protein 3.1, also known as P311, is found in neurone and muscle cells [
]. It contains a conserved PEST (Pro, Glu, Ser, and Thr) motif, which is involved in protein-protein interactions, as well as in targeting proteins for degradation by the ubiquitin/proteasome system.In addition to a potential role in neural function, P311 may be involved in regulating glioma motility [
] and could have some function in myo-fibroblast transformation and prevention of fibrosis []. It has also been identified as a potential regulator of alveolar generation [].
This is a family of bacterial sugar transporters approximately 300 residues long. Members include glucose uptake proteins [
], ribose transport proteins, and several putative and hypothetical membrane proteins probably involved in sugar transport across bacterial membranes.
BhlA is a SP-beta prophage-derived protein found in Bacillus subtilis [
,
] and other Bacilli. A related protein, UviB, has also been described in Clostridia, where it is believed to be involved in bacteriocin secretion or immunity [,
].
Coronavirus encodes two viroporins, E protein and protein 3a, which act as ion-conductive pores in planar lipid bilayers and are required for maximal SARS-CoV replication and virulence [
]. In betacoronavirus, this protein plays a role in viral egress via lysosomal trafficking [,
]. Protein 3a from SARS-CoV-2 also blocks autolysosomes formation by binding and sequestering the host component VPS39 for homotypic fusion and protein sorting (HOPS) on late endosomes. This prevents fusion of autophagosomes with lysosomes, disrupting autophagy and facilitating virus egress [].This entry represents protein 3a encoded by Orf3/3a, also known as X1, which forms homotetrameric potassium, sodium or calcium sensitive ion channels (viroporin) and may modulate virus release. It has also been shown to up-regulate expression of fibrinogen subunits FGA, FGB and FGG in host lung epithelial cells [
,
,
,
].3a protein is a pro-apoptosis-inducing protein. It localises to the endoplasmic reticulum (ER)-Golgi compartment. SARS-CoV causes apoptosis of infected cells through NLRP3 inflammasome activation, as ORF3a is a potent activator of the signals required for this activation, pro-IL-1beta gene transcription and protein maturation. This protein also promotes the ubiquitination of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) mediated by its interaction with TNF receptor-associated factor 3 (TRAF3). The expression of ORF3a induces NF-kappa B activation and up-regulates fibrinogen secretion with the consequent high cytokine production [
,
,
,
]. Another apoptosis mechanism described for this protein is the activation of the PERK pathway of unfolded protein response (UPR), which causes phosphorylation of eIF2alpha and leads to reduced translation of cellular proteins as well as the activation of pro-apoptotic downstream effectors (i.e ATF4, CHOP) [].
Members of this group are stand-alone forms of the LytTR DNA-binding domain [
]. One of them is BlpS from Streptococcus pneumoniae. BlpS is encoded together with the components of the two-component system Blp, which also contains another LytTR-containing protein, the response regulator BlpR []. The Blp system is closely related to quorum-sensing systems regulating cell density-dependent phenotypes, such as the development of genetic competence or the production of antimicrobial peptides in lactic acid bacteria, and is a peptide-sensing system that controls the blpregulon. The
blpregulon is composed of genes for regulation, synthesis, export, and processing of Blps (bacteriocin-like peptides) [
]. The exact function of BlpS is not clear.
Centromere protein I (CENP-I) is a component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation [
]. It may be involved in incorporation of newly synthesized CENP-A into centromeres via its interaction with the CENPA-NAC complex []. In humans, CENP-I is required for the localisation of CENPF, MAD1L1 and MAD2 (MAD2L1 or MAD2L2) to kinetochores and is involved in the response of gonadal tissues to follicle-stimulating hormone []. The CENP-I homologue in Schizosaccharomyces pombe, Mis6, is thought to be required for recruiting CENP-A, the centromere- specific histone H3 variant; an important event for centromere function and chromosome segregation during mitosis [
,
].
The Rop protein regulates plasmid DNA replication by modulating the initiation of transcription
of the primer RNA precursor. Processing of the precursor, RNAII, is inhibited by hydrogen bonding of RNAII to its complementary sequence in RNAI. Rop increases the affinity of RNAI for RNAII and
thus decreases the rate of replication initiation events. The 3D structure of Rop has been determined by X-ray crystallography and refined to 1.7A resolution. The 63 amino acid protein is
a homodimer, each monomer consisting almost entirely of two α-helices, the whole molecule forming a highly regular four-α-helix bundle [
]. This can be approximated by a four-stranded rope, with radius 7.0 A, a left-handed helical twist, and pitch 172.5 A. A very compact
packing of side chains in the helix interfaces of the Rop coiled-coil structure is presumed to account for its high stability [
]. The overall details of the structure have beenconfirmed by proton NMR [
,
].
Olfactory marker protein (OMP) is a highly expressed, cytoplasmic protein found in mature olfactory sensory receptor neurons of all vertebrates. OMP is a modulator of the olfactory signal transduction cascade. The crystal structure of OMP reveals a beta sandwich consisting of eight strands in two sheets with a jelly-roll topology [
]. Three highly conserved regions have been identified as possible protein-protein interaction sites in OMP, indicating a possible role for OMP in modulating such interactions, thereby acting as a molecular switch [].
This family of bacterial arginine kinases catalyse the transfer of phosphate from ATP to arginine. Protein arginine phosphorylation is involved in the regulation of many critical cellular processes, such as protein degradation, competence and stress responses [
]. Bacterial protein arginine kinase McsB main targets comprise central factors of the stress response system including the CtsR and HrcA heat shock repressors, as well as major components of the protein quality control system such as the ClpCP protease and the GroEL chaperonine []. McsB has been shown to phosphorylate and inhibit global heat shock repressor CtsR []. Furthermore, McsB is an adaptor for the ClpCP protease. McsB is activated during heat stress by autophosphorylation, allowing the controlled degradation of CtsR by ClpCP []. It is also required for de-localization of competence proteins [].
