The E. coli interleukin [IL]receptor mimic protein A (IrmA), is a small (13kDa) Uropathogenic E. coli (UPEC) protein that was originally identified in a large reverse genetic screen as a broadly protective vaccine antigen. It has a fibronectin III (FNIII)-like fold that forms a domain-swapped dimer with structural mimicry to the binding domain of the IL-2 receptor (IL-2R), the IL-4 receptor (IL-4R) and, to a lesser extent, the IL-10 receptor (IL-10R). IrmA binds to all three cytokines, with the greatest affinity observed for IL-4. It is suggested that IrmA may contribute to manipulation of the innate immune response during UPEC infection [].
The structure of TusA (also known YhhP and SirA) consists of an alpha/beta sandwich with a beta-α-β-α-β(2) fold, comprising a mixed four-stranded β-sheet stacked against two α-helices, both of which are nearly parallel to the strands of the β-sheet []. Several uncharacterised bacterial proteins (73 to 81 amino-acid residues in length) that contain a well-conserved region in their N-terminal region show structural similarity to the TusA protein, including the E. coli protein YedF (), and other members of the UPF0033 family.NOTE: TusA was previously known as SirA, but should not be confused with the sporulation inhibitor of replication protein SirA () or with the LuxR/UhpA family response regulator , also known as SirA.
This entry represents the SH3 domain of DBS.DBS, also called MCF2L or OST, functions as a Rho GTPase guanine nucleotide exchange factor (RhoGEF), facilitating the exchange of GDP and GTP. It was originally isolated from a cDNA screen for sequences that cause malignant growth. It plays roles in regulating clathrin-mediated endocytosis and cell migration through its activation of Rac1 and Cdc42 [, ]. Depending on cell type, DBS can also activate RhoA and RhoG [, ]. DBS contains a Sec14-like domain [], spectrin-like repeats, a RhoGEF or Dbl homology (DH) domain, a Pleckstrin homology (PH) domain [], and an SH3 domain.
Otoraplin, also known as MIAL (MIA-like), is specifically expressed in the cochlea and the vestibule of the inner ear and may contribute to inner ear dysfunction in humans []. It is a member of the MIA family. MIA (melanoma inhibitory activity) family members include MIA, MIAL, MIA2, and MIA3 (also called TANGO). MIA was found to be strongly expressed and secreted by malignant melanomas. It contains a domain that adopts a Src Homology 3 (SH3) domain-like fold; however, it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. Unlike classical SH3 domains, MIA does not bind proline-rich ligands [, ].
This entry represents the ribonuclease Z (RNase Z) homologue, RNase BN, from bacteria. RNase BN was considered to be an exonuclease based on its ability to remove the 3'-terminal residue of tRNAs ending in CA, CU, CCU or even CCA []. In E. coli, even though different set of enzymes are used for tRNA 3'-ends processing and RNase Z is thought to be less important than the other ribonucleases. However, E. coli cells lacking the four main enzymes of the exonucleolytic pathway (RNases T, PH, D and II) are viable, whereas further mutation of RNase BN/Z in this genetic context causes an unviable phenotype [].
This entry contains both type II and type IV pathway secretion proteins from bacteria. Proteins in this entry include VirB11 ATPase (), which is a subunit of the Agrobacterium tumefaciens transfer DNA (T-DNA) transfer system, a type IV secretion pathway required for delivery of T-DNA and effector proteins to plant cells during infection [].The type II protein secretion system (T2SS) is a sophisticated multi-protein machinery containing 12-15 different proteins []. Historically, this system was described as the main terminal branch (MTB) of the general secretory pathway (GSP), but this nomenclature is now on obsolete [].
Urotensin II (UII) is a vasoactive somatostatin-like or cortistatin-like peptide hormone. However, despite the apparent structural similarity to these peptide hormones, they are not homologous to UII. Urotensin II was first identified in fish spinal cord but later found in humans and other mammals []. In fish, UII is secreted at the back part of the spinal cord, in a neurosecretory centre called uroneurapophysa, and is involved in the regulation of the renal and cardiovascular systems []. In mammals, urotensin II is the most potent mammalian vasoconstrictor identified to date and causes contraction of arterial blood vessels, including the thoracic aorta [, , ]. This entry represents urotensin II.
This domain was first discovered in BPSL1050, a highly immunoreactive protein found in Burkholderia pseudomallei. The domain's structure consists of three helical regions which pack onto an antiparallel beta sheet, formed by four strands. The beta sheet is solvent exposed on one side and packs tightly against the three helices on the other side, generating a network of hydrophobic and aromatic interactions that contribute to tight packing of the protein. It is thought that the small loop L1, the main loop L2, and part of helix alpha-3 extending until Leu120 are the three main immunogenic sequences [].
This entry represents the N-terminal α-helical domain of the BREVIS RADIX (BRX), which was characterised as being a transcription factor in plants regulating the extent of cell proliferation and elongation in the growth zone of the root [, ]. BRX maintains a rate-limiting brassinosteroid biosynthesis enzyme expression to keep brassinosteroid biosynthesis above a critical threshold []. BRX has a ubiquitous, although quantitatively variable role in modulating the growth rate in both the root and the shoot []. This entry features a short α-helical domain, N-terminal to the repeated α-helices of the BRX domain ().
Small, non-coding RNA molecules play important regulatory roles in a variety of physiological processes in bacteria. This entry represents the N-terminal domain of the SgrR family of proteins which regulate the transcription of these sRNAs, in particular SgrS. This domain contains a helix-turn-helix motif characteristic of winged-helix DNA-binding transcriptional regulators. SgrS is a small RNA required for recovery from glucose-phosphate stress in bacteria []. In examining the regulation of SgrR expression it was found that SgrR negatively auto-regulates its own transcription in the presence and absence of stress, and thus SgrR coordinates the response to glucose-phosphate stress by binding specifically to sgrS promoter DNA [].
The Rab3 subfamily contains Rab3A, Rab3B, Rab3C, and Rab3D. All four isoforms were found in mouse brain and endocrine tissues, with varying levels of expression. Rab3A, Rab3B, and Rab3C localized to synaptic and secretory vesicles; Rab3D was expressed at high levels only in adipose tissue, exocrine glands, and the endocrine pituitary, where it is localized to cytoplasmic secretory granules []. Rab3 appears to control Ca2+-regulated exocytosis. The appropriate GDP/GTP exchange cycle of Rab3A is required for Ca2+-regulated exocytosis to occur, and interaction of the GTP-bound form of Rab3A with effector molecule(s) is widely believed to be essential for this process [].
Brefeldin is a lactone antibiotic produced by fungi such as Eupenicillum brefeldianum. It both inhibits protein transport between the endoplasmic reticulum (ER) and the Golgi apparatus, and induces retrograde transport from the Golgi to the ER, leading to protein accumulation within the ER. Screening of a deletion-strain collection for mutants sensitive or resistant to drugs that affect intracellular transport has revealed a number of mutants sensitive to brefeldin A: e.g., deletion of the BRE4 gene was shown to result in brefeldin A-sensitivity []. The BRE4 gene product is predicted to contain 10 transmembrane (TM) domains, suggesting that it is likely to be an integral membrane protein, potentially involved in intracellular vesicle transport [].
AUTS2 is a novel gene identified in a monozygotic twin pair with autism; its translation product is a large protein containing 1,295 amino acids []. Following DNA sequence analysis of autism subjects and controls, no autism-specific mutation was observed. Association and linkage analyses were also negative. It is hence considered unlikely that AUTS2 is an autism suspecptibility gene for idiopathic autism, although it may be the gene responsible for the disorder in the twins in this study []. The AUTS2 gene product shares a high level of similarity with the so-called fibrosin-1-like protein, a functionally uncharacterised polypeptide that contains C-terminal Ala-rich and Pro-rich regions.
This family of proteins was first identified in Caenorhabditis elegans [, , ], Smad proteins that act as intracellular signal transducers and transcriptional modulators activated by TGF-beta and regulates the entry into a developmentally arrested larval state known as dauer, in response to non-favorable environmental conditions. Mammalian dwarfins are phosphorylated in response to TGF-beta and are implicated in control of cell growth [, ]. The dwarfin family also includes the Drosophila protein MAD that is required for the function of decapentaplegic (DPP) and may play a role in DPP signalling. Drosophila Mad binds to DNA and directly mediates activation of vestigial by Dpp [].
Histone acetyltransferase KAT8 () has activity directed towards histones H3, H2A and H4 []and is the active component of the MSL and NSL complexes []. KAT8 autoacetylates itself on Lys-274 which is a requirement for binding to histone H4 []. In Drosophila melanogaster this protein is known as 'males-absent on the first protein' (MOF) [].The male-specific lethal (MSL) complex is a histone acetyltransferase with specificity for histone H4 'lysine-16' in chromatin. The complex consists of MOF, MSL1, MSL2, and MSL3 []. The complex was first identified in Drosophila.
The NuA4 histone acetyltransferase complex (also known as the TRRAP/TIP60-containing histone acetyltransferase complex) acetylates nucleosomal histones H4 and H2A thereby activating selected genes for transcription and is a a key regulator of transcription, cellular response to DNA damage and cell cycle control []. In yeast, where the complex was first identified, NuA4 consists of at least ACT1, ARP4, YAF9, VID21, SWC4, EAF3, EAF5, EAF6, EAF7, EPL1, ESA1, TRA1 and YNG2 []. In humans, the complex is composed of the histone acetyltransferase KAT5 (also known as TIP60) plus the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, MAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 [].This entry includes KAT5/Tip60 from animals.
This entry represents a domain found in GMP-PDE delta subunit and related proteins. GMP-PDE delta subunit was originally identified as a fourth subunit of rod-specific cGMP phosphodiesterase (PDE) (). The precise function of PDE delta subunit in the rod specific GMP-PDE complex is unclear. In addition, PDE delta subunit is not confined to photoreceptor cells but is widely distributed in different tissues. PDE delta subunit isthought to be a specific soluble transport factor for certain prenylated proteins and Arl2-GTP a regulator of PDE-mediated transport [].
This entry represents fungal proteinase inhibitors found mainly in arthropodes, including fungal protease inhibitor-1 (FPI-1) from Antheraea mylitta (Tasar silkworm). FPI1 inhibits trypsin and chymotrypsin proteases from the fungi Aspergillus oryzae and Rhizopus oryzae. However, they do not inhibit papain-like proteases from the bacterium Bacillus licheniformis []. The crystal structure of this protein was solved using the single isomorphous replacement with anomalous scattering (SIRAS), which revealed that it is a single domain protein possessing a unique fold that consists of three helices and five β-strands stabilized by a network of six disulfide bonds []. Members of this family belong to MEROPS inhibitor family I83, clan JH.
ARC3 acts as a Z-ring accessory protein involved in division site placement in chloroplast. ARC3 contains an N-terminal domain with similarities to FtsZ proteins and a C-terminal domain containing MORN (membrane occupation and recognition) motifs, linked by a novel middle domain, and was reported as a cytosolic chloroplast division component [, ]. ARC3 is distributed throughout the stroma and is also localized to a midplastid ring-like structure where it is recruited to the middle of the plastid by PARC6, which facilitates Z-ring remodeling during chloroplast division by promoting Z-ring dynamics. This reveals a novel function for MORN domains in regulating protein-protein interactions [].
This family includes Melanocyte protein PMEL (also known as PMEL-17), Transmembrane glycoprotein NMB (GPNMB) and Transmembrane protein 130, previously described as melanocyte protein PMEL-17-related family. Regarding the highly conserved domain architecture of these family members, including the PKD, KLD and transmembrane (TM) domains, the name was updated and now referred to as PKD- and KLD-Associated Transmembrane (PKAT) protein family []. TMEM130 has been identified as the most ancient paralogue of PMEL and GPNMB.PMEL and GPNMB share overlapping phenotypes and disease associations, such as melanin-based pigmentation, cancer, neurodegenerative disease and glaucoma.
This entry includes Focadhesin from animals and RST1 (RESURRECTION 1) from plants. Focadhesin (FOCAD) is a focal adhesion protein with potential tumour suppressor function in gliomas []. RST1 was originally identified in a genetic screen for factors involved in the biosynthesis of epicuticular waxes []. Later, RST1 and RST1 INTERACTING PROTEIN (RIPR) have been shown to act as cofactors of the cytoplasmic exosome and the Ski complex in plants []. RST1 is involved in the suppression of siRNA-mediated silencing of transgenes and certain endogenous transcripts [].
CHASE6 was originally described as a two-partite extracellular (periplasmic) sensor domain found in histidine kinases and HD-GYP-type c-di-GMP-specific phosphodiesterases []and assigned to COG4250 in the COG database. Subsequently, its N-terminal part has been described as a separate DICT (DIguanylate Cyclases and Two-component systems) domain () (Aravind L., Iyer LM, Anantharaman V. (2010) Natural history of sensor domains in the bacterial signalling systems. In: Sensory Mechanisms in Bacteria: Molecular Aspects of Signal Recognition ((Spiro S, Dixon R, eds), pp. 1-38. Caister Academic Press, Norfolk, UK). The current entry contains only the C-terminal part of the original CHASE6 domain described in [], which is found primarily in cyanobacteria.
The unusual mucin, epiglycanin, is membrane-bound at the C terminus but has a long region of this tandem-repeat at the N terminus []. It was the first mucin identified to be associated with the malignant behaviour of carcinoma cells []. Mouse Muc21/epiglycanin is thought to be a highly glycosylated molecule, which makes it likely that its function is dependent on its glycoforms. Cells expressing Muc21 are significantly less adherent to each other and to extracellular matrix components than control cells, and this loss of adhesion is mediated by the tandem-repeat portion of Muc21 [].
This entry represents a repeat of about 40 amino acids found in a variety of archaea and bacteria which can be present in up to 14 copies per protein. The archaeal species Methanosarcina mazei (Methanosarcina frisia) contains several predicted surface layer proteins (SLPs) containing tandem copies of this repeat []. The crystal structure of one of these proteins (), containing seven tandem copies of this repeat, was examined. Individually, these repeats form four-stranded beta blades, while the seven copies together form a seven-bladed beta propeller domain. This repeat shows sequence similarity to the WD-40 repeat () and may play a similar role, serving as a rigid scaffold for protein interactions.
Junction-mediating and regulatory protein (JMY) is a vertebrate protein that was first identified as a transcriptional co-activator of p53 []. It is a regulator of both transcription and actin filament assembly [, , ]. In the nucleus it acts as a transcriptional coactivator and promotes programmed cell death in response to DNA damage [], whereas in the cytoplasm it promotes actin filament assembly []. JMY can either initiate actin filament formation by binding and activating the Arp2/3 complex or nucleate filaments directly in a SPIRE-like fashion [, ]. In both cases, the JMY's actin-regulatory activity relies on a cluster of three actin-binding WH2 domains at its C terminus [].
The Ska complex is an essential mitotic component required for accurate cell division in human cells. It is an important kinetochore component involved in the formation of kinetochore-microtubule interactions, and together with the Ndc80 complex couples chromosome movement to microtubule depolymerization []. The complex is composed of three subunits: Ska1, Ska2, and Ska3.Ska3 was the last subunit of the complex identified []. Ska3 accumulates on kinetochores in prometaphase after nuclear envelope breakdown. During mitosis, it is required for the maintenance of chromosome cohesion and may play an important role in silencing the spindle checkpoint [].
This entry represents a domain found at the N terminus of FRAS1-related extracellular matrix proteins (also known as Frem related proteins) predominantly in chordates. In humans, the FRAS1-related extracellular matrix protein 1 was reported to be essential for the normal adhesion of the embryonic epidermis []. FRAS1-related extracellular matrix protein 2 is involved in the development of eyelids and the anterior segment of the eyeballs and has been related to cryptophthalmos (a rare congenital disorder characterized by ocular dysplasia with eyelid malformation) [, ].
Transmembrane protein 131-like (TMEM131L) was identified as a negative regulator of thymocyte proliferation that acts through mixed Wnt-dependent and independent mechanisms. It has two isoforms, L and S, which have different subcellular localisation. L isoform, the membrane-associated form, inhibits canonical Wnt/beta-catenin signalling through the induction of lysosome-dependent degradation of the active phosphorylated form of the LRP6 coreceptor. This protein contains three conserved homology domains (CHD1, 2 and 3), a transmembrane region and a C-terminal serine-rich region []. This entry represents a conserved domain found in TMEM131 and TMEM131L. This domain is C-terminal to the CHD1 domain.
Noggin was first discovered by its ability to induce secondary axis formation in Xenopus embryos []. It is a secreted homodimeric glycoprotein that serves as a BMP (bone morphogenetic protein) antagonist [, ]. It has been found that noggin arrests the differentiation of stromal cells, preventing cellular maturation []. In humans increased noggin activity results in skeletal dysplasia such as proximal symphalangism (SYM1) and multiple synostosis syndrome 1 (SYNS1) []. Noggin maintains prolonged growth of human embryonic stem cells in vitro and regulates the stem cell niche during neurogenesis [, ].
This entry represents the cell cycle link protein Clink from Banana bunchy top virus (BBTV) [], which was identified as a suppressor of RNA silencing. It interacts with retinoblastoma-related proteins (pRB) and S-phase kinase-associated protein 1 (SKP1). Clink contains LxCxE and F-box motifs that mediate the interactions with the respective proteins and the capacity of Clink to bind pRB correlates with its ability to stimulate viral replication. pRB is a key cell cycle regulator, which represses onset and progression into S-phase by interacting with a wide range of cell cycle-related proteins.
AMIGO-1 was identified as a protein induced in neurons by the neurite-promoting protein amphoterin. It is highly expressed in the nervous system. AMIGO-1 has a role in regulating dendritic growth and neuronal survival []. It is involved in fasciculation and myelination of developing neural axons, as well as in regeneration and plasticity of the adult fibre tracts []. It displays a homophilic and heterophilic binding mechanism, which suggest a role as a cell adhesion molecule []. AMIGO acts as a function-modulating auxiliary subunit for potassium channel alpha-subunit Kv2.1, which is highly expressed in the brain [].
This small motif is found at the N terminus of Kank proteins and has been called the KN (for Kank N-terminal) motif. This protein is found in eukaryotes. Proteins in this family are typically between 413 to 1202 amino acids in length. This protein is found associated with . This protein has two conserved sequence motifs: TPYG and LDLDF. Kank1 was obtained by positional cloning of a tumor suppressor gene in renal cell carcinoma, while the other members were found by homology search. The family is involved in the regulation of actin polymerisation and cell motility through signaling pathways containing PI3K/Akt and/or unidentified modulators/effectors [].
This entry represents a group of Rab GTPase-activating proteins (RabGAPs), including TBC20 from humans and Gyp8 from Saccharomyces cerevisiae. They contain the TBC/rab GTPase-activating protein (GAP) domain.TBC20 can accelerate the intrinsic GTP hydrolysis rate by more than five orders of magnitude for Rab1 and Rab2 small GTPase families [, , ]. This protein have been related to numerous diseases due to its critical role in cellular processes [, , ]. It was also seen to be essential for the replication and assembly of hepatitis C virus (HCV) [].Gyp8 is involved in the regulation of ER to Golgi vesicle transport in yeast mainly by activating the Ypt/Rab-GTPase Ypt1 [].
This family consists of several RIB43A-like eukaryoticproteins. Ciliary and flagellar microtubules contain a specialised set of protofilaments, termed ribbons, that are composed of tubulin and several associated proteins. RIB43A was first characterised in the unicellular biflagellate, Chlamydomonas reinhardtii although highly related sequences are present in several higher eukaryotes including humans. The function of this protein is unknown although the structure of RIB43A and its association with the specialised protofilament ribbons and with basal bodies is relevant to the proposed role of ribbons in forming and stabilising doublet and triplet microtubules and in organising their three-dimensional structure. Human RIB43A homologues could represent a structural requirement in centriole replication in dividing cells [].
The small Ras-like GTPase Ran plays an essential role in the transport of macromolecules in and out of the nucleus and has been implicated in spindle and nuclear envelope formation during mitosis in higher eukaryotes. The Saccharomyces cerevisiae ORF YGL164c encoding a novel RanGTP-binding protein, termed Yrb30p was identified. The protein competes with S. cerevisiae RanBP1 (Yrb1p) for binding to the GTP-bound form of S. cerevisiae Ran (Gsp1p) and is, like Yrb1p, able to form trimeric complexes with RanGTP and some of the karyopherins [].
RNA (C5-cytosine) methyltransferases (RCMTs) catalyse the transfer of a methyl group to the 5th carbon of a cytosine base in RNA sequences to produce C5-methylcytosine. RCMTs use the cofactor S-adenosyl-L-methionine (SAM) as a methyl donor []. The catalytic mechanism of RCMTs involves an attack by the thiolate of a Cys residue on position 6 of the target cytosine base to form a covalent link, thereby activating C5 for methyl-group transfer. Following the addition of the methyl group, a second Cys residue acts as a general base in the beta-elimination of the proton from the methylated cytosine ring. The free enzyme is restored and the methylated product is released [].Numerous putative RCMTs have been identified in archaea, bacteria and eukaryota [, ]; most are predicted to be nuclear or nucleolar proteins []. The Escherichia coli Ribosomal RNA Small-subunit Methyltransferase Beta (RSMB) FMU (FirMicUtes) represents the first protein identified and characterised as a cytosine-specific RNA methyltransferase. RSMB was reported to catalyse the formation of C5-methylcytosine at position 967 of 16S rRNA [, ].A classification of RCMTs has been proposed on the basis of sequence similarity []. According to this classification, RCMTs are divided into 8 distinct subfamilies []. Recently, a new RCMT subfamily, termed RCMT9, was identified []. Members of the RCMT contain a core domain, responsible for the cytosine-specific RNA methyltransferase activity. This 'catalytic' domain adopts the Rossman fold for the accommodation of the cofactor SAM []. The RCMT subfamilies are also distinguished by N-terminal and C-terminal extensions, variable both in size and sequence [].
Aromatic polyketides are assembled by a type II (iterative) polyketide synthases (PKSs) in bacteria. Type II PKS complexes consist of several monofunctional or bifunctional proteins which produce polyketide chains of variable but defined length from a specific starter unit and a number of extender units. They also specify the initial regiospecific folding and cyclization pattern of nascent polyketides either through the action of a cyclase (CYC) subunit or through the combined action of site-specific ketoreductase and CYC subunits [, ]. This family represents a number of cyclases involved in polyketide synthesis in a number of actinobacterial species.Tetracenomycin F2 cyclase (TcmI) catalyses an aromatic rearrangement in the biosynthetic pathaway of tetracenomycin C from Streptomyces glaucescens. The protein is a homodimer where each subunit forms a beta-α-β fold belonging to the ferrodoxin fold superfamily []. Four strands of antiparallel sheets and a layer of alpha helices create a cavity which was proposed to be the active site. This structure shows strong topological similarity to a polyketide monoxygenase () from S. coelicolor which functions in the actinorhodin biosynthesic pathway []. It was suggested, therefore, that this fold is well suited to serve as a framework for rearrangements and chemical modification of polyaromatic substrates.
The THUMP domain (named afterTHioUridine synthases, RNA Methylases and Pseudouridinesynthases) is a module of 100-110 amino acid residues which is involvedRNA metabolism. It is shared by enzymes involved in at least three unrelated types of RNA-modification, namely methylation, pseudouridylation and thiouridylation. The THUMP domain can occur in stand-alone form orin association with a variety of catalytic domains, likemethylase, pseudo U-synthase or rhodanese. THUMP is anancient domain that apparently evolved prior to the divergence of the primary divisions oflife. It was initially predicted to have RNA-binding capacity but it was shown later that it associates with the adjacent FLD domain () to display the RNA-binding ability, leading to the delivery of a variety of RNA modification enzymes to their targets. The domain adopts an α/β fold, with two helices packed against a β-sheet [, , , ].Some proteins known to contain a THUMP domain are listed below:Bacterial and archaeal thiI-like 4-thiouridine synthases (also known as tRNA sulfurtransferases or Thiamine biosynthesis protein ThiI).Bacterial, archaeal and eukaryotic RNA methyltransferases.Archaeal pseudouridine synthases (PSUSs).Several uncharacterised proteins.
This family consists of proteins from different gene families: Ndr1/RTP/Drg1, Ndr2, and Ndr3. Their similarity was previously noted []. The precise molecular and cellular function of members of this family is still unknown, yet they are known to be involved in cellular differentiation events. The Ndr1 group was the first to be discovered. Their expression is repressed by the proto-oncogenes N-myc and c-myc, and in line with this observation, Ndr1 protein expression is down-regulated in neoplastic cells, and is reactivated when differentiation is induced by chemicals such as retinoic acid. Ndr2 and Ndr3 expression is not under the control of N-myc or c-myc. Ndr1 expression is also activated by several chemicals: tunicamycin and homocysteine induce Ndr1 in human umbilical endothelial cells; nickel induces Ndr1 in several cell types. Members of this family are found in wide variety of multicellular eukaryotes, including an Ndr1 type protein in Helianthus annuus (Common sunflower), known as Sf21. Interestingly, the highest scoring matches in the noise are all alpha/beta hydrolases (), suggesting that this family may have an enzymatic function.
This group represents alpha-1B-glycoproteins and several leukocyte immunoglobulin-like receptors. There are five domains in human alpha 1B-glycoprotein. Mongoose antihemorrhagic factor (AHF1) is a protein, which is homologous to human alpha 1BG, and a supergene family of immunoglobulins []. Alpha-1B-glycoproteins have been found associated with a number of diseases. They have been detected in the urine of children with steroid-resistant minimal change nephrotic syndrome (SRINS) []. It is also found associated with bladder cancer, having been detected in all tumor-bearing patient samples but not samples obtained from non-tumor-bearing individuals []. When the 1694 bp was cloned from human liver Marathon cDNA, which is the alpha-1B glycoprotein precursor gene, it was found that it may be a novel member of immunoglobulin superfamily and could be involved in cell recognition and the regulation of cell behavior [].Polymorphism of Alpha-1-B-glycoprotein (A1BG) has been found in the plasma of several human populations of the Indian subcontinent []. Human leukocyte antigen-G (HLA-G) is a non-classical HLA class-I molecule that is expressed by placental trophoblast cells. HLA-G probably stimulates leukocyte immunoglobulin-like receptor B1 (LILRB1) receptors on decidual leukocytes. In this way, a foetus may affect the local maternal immune response []. Human killer immunoglobulin-like receptor (KIR) genes are important for restraining natural killer cytotoxicity toward cells with autologous HLA, while targeting cells lacking or expressing low levels of self-HLA molecules [].LILRB1 is expressed by most leukocytes and LILRB2 is expressed primarily by monocytes, macrophages and dendritic cells [].
This entry represents a subset of the YdjC-like family of uncharacterised proteins. The Acidithiobacillus ferrooxidans ATCC 23270 protein (AFE_0976) is encoded in the same locus as the genes for squalene-hopene cyclase (SHC, ) and other proteins associated with the biosynthesis of hopanoid natural products. Similarly, in Ralstonia eutropha (strain JMP134) (Alcaligenes eutrophus) this protein (Reut_B4902) is encoded adjacent to the genes for HpnAB, IspH and HpnH (), although SHC itself is encoded elsewhere in the genome. Notably, this protein (here named HpnK) and three others form a conserved set (HpnIJKL) which occurs in a subset of all genomes containing the SHC enzyme. This relationship was discerned using the method of partial phylogenetic profiling []. This group includes Zymomonas mobilis, the organism where the initial hopanoid biosynthesis locus was described consisting of the genes for HpnA-E and SHC (HpnF) []. Continuing past SHC are found genes encoding a phosphorylase enzyme (ZMO0873, i.e. HpnG, ) and a radical SAM enzyme (ZMO0874), HpnH. Although discontinuous in Z. mobilis, we continue the gene symbol sequence with HpnIJKL.
Aurora kinase was discovered by Glover and colleagues in a screen for genes required to maintain the centrosome cycle in Drosophila []. Its yeast homologue Ipl1 (also known as spindle assembly checkpoint kinase) was found to regulate chromosome segregation []. Subsequently, three mammal Aurora kinases, Aurora A, B and C, have been identified. They are highly conserved serine/threonine kinases that regulate chromosomal alignment and segregation during mitosis and meiosis []. They all contain a protein kinase domain and a destruction box (D-box) recognised by the multi-subunit E3-ubiquitin ligase anaphase promoting complex/cyclosome (APC/C), which mediates their proteasomal degradation. However, their N-terminal domains share little sequence identity and confer unique protein-protein interaction abilities among the Aurora kinases []. Functionally, Aurora A associates with centrosome, while Aurora B and Aurora C are parts of the chromosome passenger complex (CPC) [, ]. Aurora C plays a role in the meiotic cell cycle, but does not seem to be essential for cell divisions in somatic cells []. This entry also includes a number of uncharacterised proteins, predominantly from bacteria.
Sorting nexins (SNXs) are a diverse group of cellular trafficking proteins that are unified by the presence of a phospholipid-binding motif, the PX domain. The ability of these proteins to bind specific phospholipids, as well as their propensity to form protein-protein complexes, points to a role for these proteins in membrane trafficking and protein sorting []. Members of this group also contain coiled-coil regions within their large C-terminal domains and a BAR domain, whose function has been defined as a dimerisation motif, as sensing and inducing membrane curvature, and/or likely to bind to small GTPases [].This entry includes SNX5, SNX6 and SNX32 (also known as SNX6B).SNX5 contains a BAR domain that is C teminus to the PX domain. SNX5 plays a role in macropinocytosis []and in the internalisation of EGFR after EGF stimulation [].SNX6 was found to interact with members of the transforming growth factor-beta family of receptor serine/threonine kinases. Strong heteromeric interactions were also seen among SNX1, -2, -4, and -6, suggesting the formation in vivoof oligomeric complexes. SNX6 is localized in the cytoplasm where it is thought to target proteins to the trans-Golgi network []. In addition, SNX6 was found to be translocated from the cytoplasm to nucleus by Pim-1, an oncogene product of serine/threonine kinase. This translocation is not affected by Pim-1-dependent phosphorylation, but the functional significance is unknown [].
The JmjN and JmjC domains are two non-adjacent domains which have been identified in the jumonji family of transcription factors. Although it was originally suggested that the JmjN and JmjC domains always co-occur and might form a single functional unit within the folded protein, the JmjC domain was later found without the JmjN domain in organisms from bacteria to human [, , ].Proteins containing JmjC domain are predicted to be metalloenzymes that adopt the cupin fold and are candidates for enzymes that regulate chromatin remodelling []. The cupin fold is a flattened β-barrel structure containing two sheets of five antiparallel β-strands that form the walls of a zinc-binding cleft. Based on the crystal structure of JmjC domain containing protein FIH and JHDM3A/JMJD2A, the JmjC domain forms an enzymatically active pocket that coordinates Fe(III) and alphaKG. Three amino-acid residues within the JmjC domain bind to the Fe(II) cofactor and two additional residues bind to alphaKG []. JmjC domains were identified in numerous eukaryotic proteins containing domains typical of transcription factors, such as PHD, C2H2, ARID/BRIGHT and zinc fingers [, ]. The JmjC has been shown to function in a histone demethylation mechanism that is conserved from yeast to human []. JmjC domain proteins may be protein hydroxylases that catalyse a novel histone modification []. The human JmjC protein named Tyw5p unexpectedly acts in the biosynthesis of a hypermodified nucleoside, hydroxy-wybutosine, in tRNA-Phe by catalysing hydroxylation [].
The Tropomodulin (Tmod) family consist of four Tmods (Tmods 1-4) and three larger variants termed leiomodins (Lmods 1-3), which are expressed in a tissue-specific and developmentally regulated fashion []. Members of the Tmod family are actin filament pointed-end-capping proteins that regulate actin subunit association and dissociation from pointed ends in a tropomyosin-dependent manner [].Tropomodulin1 (Tmod1) was originally known to as E-Tmod, as it was first identified as a binding partner of tropomyosin (TM) in red blood cells (RBC) []. Tmod1 is predominantly expressed in terminally differentiated, post-mitotic cells (such as RBCs, lens fibre cells, neurons, andstriated muscle). Tmod1 binds with F-actin []. It is essential for stabilising F-actin at cell-cell junctions, which may be required for maintenance of cell shapes during embryonic cardiac morphogenesis []. It also regulates actin dynamics to control the precise lengths of the long alpha/beta tropomyosin-coated actin filaments in mature cardiac myofibrils [, ]. Tmod1 and Tmod4 maintain thin filament stability and correctly specified thin filament lengths in cardiac muscles via their interactions with terminal tropomyosins and their ability to regulate actin subunit exchange at pointed ends []. Tmod1's structure has been solved [].
Activator protein-2 (AP-2) transcription factors constitute a family of closely related and evolutionarily conserved proteins that bind to the DNA consensus sequence 5'-GCCNNNGGC-3' and stimulate target gene transcription [, ]. Five different isoforms of AP-2 have been identified in mammals, termed AP-2 alpha, beta, gamma, delta and epsilon. Each family member shares a common structure, possessing a proline/glutamine-rich domain in the N-terminal region, which is responsible for transcriptional activation [], and a helix-span-helix domain in the C-terminal region, which mediates dimerisation and site-specific DNA binding [].The AP-2 family have been shown to be critical regulators of gene expression during embryogenesis. They regulate the development of facial prominence and limb buds, and are essential for cranial closure and development of the lens [, ]; they have also been implicated in tumorigenesis. AP-2 protein expression levels have been found to affect cell transformation, tumour growth and metastasis, and may predict survival in some types of cancer [, ]. Mutations in human AP-2 have been linked with bronchio-occular-facial syndrome and Char Syndrome, congenital birth defects characterised by craniofacial deformities and patent ductus arteriosus, respectively []. AP-2 beta was originally isolated by cDNA screening of a human genomic library []. The protein was designated AP-2 beta on the basis of its high sequence similarity to AP-2 alpha, its site-specific DNA binding, and itsability to stimulate transcription []. Defects in AP-2 beta have been shownto cause Char syndrome, an autosomal dominant trait characterised by patentductus arteriosus, facial dysmorphism and hand anomalies.
This family includes the highly conserved mitochondrial and bacterial proteins Sdh5/SDHAF2/SdhE.Both yeast and human Sdh5/SDHAF2 interact with the catalytic subunit of the succinate dehydrogenase (SDH) complex, a component of both the electron transport chain and the tricarboxylic acid cycle. Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor). Mutational inactivation of Sdh5 confers tumor susceptibility in humans []. Bacterial homologues of Sdh5, termed SdhE, are functionally conserved being required for the flavinylation of SdhA and succinate dehydrogenase activity. Like Sdh5, SdhE interacts with SdhA. Furthermore, SdhE was characterised as a FAD co-factor chaperone that directly binds FAD to facilitate the flavinylation of SdhA. Phylogenetic analysis demonstrates that SdhE/Sdh5 proteins evolved only once in an ancestral alpha-proteobacteria prior to the evolution of the mitochondria and now remain in subsequent descendants including eukaryotic mitochondria and the alpha, beta and gamma proteobacteria [].This family was previously annotated in Pfam as being a divergent TPR repeat but structural evidence has indicated this is not true.
Aromatic polyketides are assembled by a type II (iterative) polyketide synthases (PKSs) in bacteria. Type II PKS complexes consist of several monofunctional or bifunctional proteins which produce polyketide chains of variable but defined length from a specific starter unit and a number of extender units. They also specify the initial regiospecific folding and cyclization pattern of nascent polyketides either through the action of a cyclase (CYC) subunit or through the combined action of site-specific ketoreductase and CYC subunits [, ]. This superfamily represents a number of cyclases involved in polyketide synthesis in a number of actinobacterial species.Tetracenomycin F2 cyclase (TcmI) catalyses an aromatic rearrangement in the biosynthetic pathaway of tetracenomycin C from Streptomyces glaucescens. The protein is a homodimer where each subunit forms a beta-α-β fold belonging to the ferrodoxin fold superfamily []. Four strands of antiparallel sheets and a layer of alpha helices create a cavity which was proposed to be the active site. This structure shows strong topological similarity to a polyketide monoxygenase () from S. coelicolor which functions in the actinorhodin biosynthesic pathway []. It was suggested, therefore, that this fold is well suited to serve as a framework for rearrangements and chemical modification of polyaromatic substrates.
The crystal structure of two of these members shows that this domain has a ferredoxin like fold and is likely to exists as at least homodimers. Sulphate ions are located at the dimer interfaces, which are thought to confer additional stability. Although the function of this domain remains to be identified, its structure suggests a role in protein-protein interactions possibly regulated by the binding of small-molecule ligands []. Solution of the structure of the hyperthermophilic anaerobic Thermotoga maritima sequence, (), shows that this has a beta-α-β-beta-α-β ferredoxin-like fold and assembles as a homotetramer. It was possible to identify a pocket in each monomer that bound an unidentified ligand. It was also found that it bound charged thiamine though not hydroxymethyl pyrimidine. Under oxidative conditions this bacterium is under stress, and the transcriptional unit within which this protein is expressed is up-regulated in these conditions, suggesting that the chelation of cytoplasmic thaimine is part of the response mechanism to such oxidatvie stress, which is mediated by this family [].
Enzymes containing the cyclodeaminase domain function in channelling one-carbon units to the folate pool. In most cases, this domain catalyses the cyclisation of formimidoyltetrahydrofolate to methenyltetrahydrofolate as shown in reaction (1). In the methylotrophic bacterium Methylobacterium extorquens, however, it catalyses the interconversion of formyltetrahydrofolate and methylenetetrahydrofolate [],as shown in reaction (2)(1) 5-formimidoyltetrahydrofolate = 5,10-methenyltetrahydrofolate + NH(3)(2) 10- formyltetrahydrofolate = 5,10-methenyltetrahydrofolate + H(2)OIn prokaryotes, this domain mostly occurs on its own, while in eukaryotes it is fused to a glutamate formiminotransferase domain (which catalyses the previous step in the pathway) to form the bifunctional enzyme formiminotransferase-cyclodeaminase []. The eukaryotic enzyme is a circular tetramer of homodimers [], while the prokaryotic enzyme is a dimer [, ].The crystal structure of the cyclodeaminase enzyme () from Thermaotoga maritima has been studied []. It is a homodimer, where each monomer is composed of six alpha helices arranged in an up and down helical bundle, forming a novel fold. The location of the active site is not known, but sequence alignments revealed two clusters of conserved residues located in a deep pocket within the dimmer interface. This pocket was large enough to accommodate the reaction product and it was postulated that this is the active site.
Neuropeptide S (NPS) is a neuropeptide found in human and mammalian brain and is mainly produced by neurons in the amygdala, expression has also been found in other areas of the brain such as the lateral parabrachial nucleus and hypothalamus [, , , ]. Overall, the expression of NPS is restricted in the brain, but it has been found in peripheral sites that include mostly endocrine tissues such as thyroid, mammary gland, salivary gland and testis. Neuropeptide S has been was found to suppress anxiety [, , , ]and appetite [, ], induce wakefulness and hyperactivity, including hyper-sexuality [, , ], and plays a significant role in the extinction of conditioned fear. Central administration of NPS was also found to modulate hypothalamic-pituitary-adrenal axis activity []. This entry represents the neuropeptide S receptor (NPSR), which is a member of the rhodopsin G protein-coupled receptor family []and it binds NPS [, , ]. Like the tissue distribution of NPS, the neuropeptide S receptor is widely distributed in the brain, with high expression levels in cortex, hypothalamus, amygdala and multiple midline thalamic nuclei. Many of these areas have been functionally associated processing of emotional behaviour, promoting arousal and anxiolytic-like effects [, ]. In addition to this, activation of NPSR in the airway epithelium has a number of effects including up-regulation of matrix metalloproteinases which are involved in the pathogenesis of asthma []. It is also thought to be involved in irritable bowel syndrome [].
Urotensin II (UII) is a vasoactive somatostatin-like or cortistatin-like peptide hormone. However, despite the apparent structural similarity to these peptide hormones, they are not homologous to UII. Urotensin II was first identified in fish spinal cord but later found in humans and other mammals []. In fish, UII is secreted at the back part of the spinal cord, in a neurosecretory centre called uroneurapophysa, and is involved in the regulation of the renal and cardiovascular systems []. In mammals, urotensin II is the most potent mammalian vasoconstrictor identified to date and causes contraction of arterial blood vessels, including the thoracic aorta [, , ]. The urotensin II receptor is a rhodopsin-like G-protein coupled receptor, which binds urotensin-II []. The receptor was previously known as GPR14, or sensory epithelial neuropeptide-like receptor (SENR) []. The UII receptor is expressed in the CNS (cerebellum and spinal cord), skeletal muscle, pancreas, heart, endothelium and vascular smooth muscle []. It is involved in the pathophysiological control of cardiovascular function and may also influence CNS and endocrine functions [, ]. Binding of urotensin II to the receptor leads to activation of phospholipase C, through coupling to Gq/11 family proteins. The resulting increase in intracellular calcium may cause the contraction of vascular smooth muscle [].This entry represents the urotensin II receptor.
This entry represents the DEP (Dishevelled, Egl-10 and Pleckstrin) domain, a globular domain of about 80 residues that is found in over 50 proteins involved in G-protein signalling pathways. It was named after the three proteins it was initially found in:Dishevelled (Dsh and Dvl), which play a key role in the transduction of the Wg/Wnt signal from the cell surface to the nucleus; it is a segment polarity protein required to establish coherent arrays of polarized cells and segments in embryos, and plays a role in wingless signalling.Egl-10, which regulates G-protein signalling in the central nervous system. Pleckstrin, the major substrate of protein kinase C in platelets; Pleckstrin contains two PH domains flanking the DEP domain.Mammalian regulators of G-protein signalling also contain these domains, and regulate signal transduction by increasing the GTPase activity of G-protein alpha subunits, thereby driving them into their inactive GDP-bound form. It has been proposed that the DEP domain could play a selective role in targeting DEP domain-containing proteins to specific subcellular membranous sites, perhaps even to specific G protein-coupled signaling pathways [, ]. Nuclear magnetic resonance spectroscopy has revealed that the DEP domain comprises a three-helix bundle, a β-hairpin 'arm' composed of two β-strands and two short β-strands in the C-terminal region [].
DNA ligase (polydeoxyribonucleotide synthase) is the enzyme that joins two DNA fragments by catalysing the formation of an internucleotide ester bond between phosphate and deoxyribose. It is active during DNA replication, DNA repair and DNA recombination. There are two forms of DNA ligase, one requires ATP (), the other NAD (), the latter being restricted to eubacteria. Eukaryotic, archaebacterial, viral and some eubacterial DNA ligases are ATP-dependent. The first step in the ligation reaction is the formation of a covalent enzyme-AMP complex. The co-factor ATP is cleaved to pyrophosphate and AMP, with the AMP being covalently joined to a highly conserved lysine residue in the active site of the ligase. The activated AMP residue is then transferred to the 5'phosphate of the nick, before the nick is sealed by phosphodiester-bond formation and AMP elimination [, ].This domain superfamily is found in many but not all ATP-dependent DNA ligase enzymes (). It is thought to be involved in DNA binding and in catalysis. In human DNA ligase I (), and in Saccharomyces cerevisiae (Baker's yeast) (), this region was necessary for catalysis, and separated from the amino terminus by targeting elements. In Vaccinia virus () this region was not essential for catalysis, but deletion decreases the affinity for nicked DNA and decreased the rate of strand joining at a step subsequent to enzyme-adenylate formation [].
Angiogenesis, the process whereby new blood vessels are formed by amechanism of sprouting from existing vessels, has recently been the subjectof intense research. Angiostatin, a proteolytically generated fragment ofplasminogen consisting of the first four kringle domains, is a potentangiogenesis inhibitor. Whilst this protein has been known for some time,until recently its mechanism of action was unknown. A functional angiostatin-binding protein has been described that inhibits endothelial cell motilityand proliferation, key stages in angiogenesis []. This protein has beennamed angiomotin.Angiomotin was identified via a yeast two-hybrid screen for proteins thatinteract with angiostatin. It is a 72kDa cell-surface associated proteinexpressed in endothelium and other tissues where angiogenesis occurs, suchas placenta and tumours. It appears that angiomotin stimulates angiogenesisby increasing cell motility and that binding of angiostatin inhibits thisprocess []. Two paralogues of angiomotin have recently been cloned andtheir amino acid sequences determined. Together with angiomotin, theseproteins form a novel family bearing little sequence similarity to otherknown proteins. Sequence analysis has revealed putative coiled-coil and PDZ-binding domains [].
This entry includes tuftelin-interacting protein 11 (TFP11) from humans, septin/tuftelin-interacting protein 1 (STIP1) from Drosophila melanogaster and Ntr1 (also known as Spp382) from budding yeasts.Ntr1 forms the NTR complex (NineTeen Complex) with Ntr2 and Prp43 (a DExD/H-box RNA helicase) that catalyses disassembly of ntron-lariat spliceosomes (ILS) and defective earlier spliceosomes. Ntr1 has been shown to interact with Prp43 through the N-terminal G-patch domain, with Ntr2 through a middle region, and with itself through the carboxyl half of the protein []. The G-patch domain of Ntr1 activates Prp43 for spliceosome disassembly, while its C-terminal domain may have a safeguarding role preventing Prp43-mediated disassembly of wild-type spliceosomes other than the IL spliceosome [, ].Septin and tuftelin interacting proteins (STIPs) are G-patch domain proteins involved in spliceosome disassembly []. The mouse protein, known as TFT11 was originally identified as a protein interacting with tuftelin, one of the presumed enamel matrix proteins []. The Drosophila protein STP1 was originally identified as a septin-interacting protein []. In both cases these interactions were identified by a yeast two-hybrid system and their function and direct physical association were not characterised. Subsequent studies show that these proteins are widely expressed and function as splicing factors [, ]. STIP is essential for embryogenesis in Caenorhabditis elegans [].
This entry includes pannexins from vertebrates and innexins from invertebrate []. Gap junctions are composed of membrane proteins,which form a channel permeable for ions and small molecules connectingcytoplasm of adjacent cells. Although gap junctions provide similar functionsin all multicellular organisms, until recently it was believed thatvertebrates and invertebrates use unrelated proteins for this purpose. Whilethe connexins family of gap junction proteins is well-characterised in vertebrates, no homologues have been found in invertebrates. Inturn, gap junction molecules with no sequence homology to connexins have beenidentified in insects and nematodes. It has been suggested that these proteinsare specific invertebrate gap junctions, and they were thus named innexins(invertebrate analog of connexins) []. As innexin homologues were recently identified in other taxonomic groups including vertebrates, indicating their ubiquitous distribution in the animal kingdom, they were called pannexins(from the Latin pan-all, throughout, and nexus-connection, bond) [, , ].Genomes of vertebrates carry probably a conserved set of 3 pannexin paralogs(PANX1, PANX2 and PANX3). Invertebrate genomes may contain more than a dozenpannexin (innexin) genes. Vinnexins, viral homologues of pannexins/innexins,were identified in Polydnaviruses that occur in obligate symbioticassociations with parasitoid wasps. It was suggested that virally encodedvinnexin proteins may function to alter gap junction proteins in infected hostcells, possibly modifying cell-cell communication during encapsulationresponses in parasitized insects [, ]. Structurally pannexins are simillar to connexins. Both types of proteinconsist of a cytoplasmic N-terminal domain, followed by four transmembranesegments that delimit two extracellular and one cytoplasmic loops; the C-terminal domain is cytoplasmic.
A family containing a number of integral membrane proteins is named after TerC protein. TerC has been implicated in resistance to tellurium, and may be involved in efflux of tellurium ions. The tellurite-resistant Escherichia coli strain KL53 was found during testing of a group of clinical isolates for antibiotic and heavy metal ion resistance []. The determinant of the strain's tellurite resistance was located on a large conjugative plasmid, and analyses showed the genes terB, terC, terD and terE were essential for conservation of this resistance. Members of this family contain a number of conserved aspartates which may be involved in metal ion binding.A TerC homologue is known from the chloroplast thylakoid membrane from Arabidopsiswhich is important for thylakoid membrane biogenesis in the developing chloroplast []; it is required for insertion of proteins into the thylakoid membrane [].This entry represents a subset of TerC proteins which are mostly encoded on genes preceded by a structured RNA element known as the yybP-ykoY leader. The yybP-ykoY leader (also known as SraF) may function in the regulation of these genes as riboswitch []. This entry also includes the putative membrane-bound redox modulator Alx [].
Thrombospondins are multimeric multidomain glycoproteins that function at cell surfaces and in the extracellular matrix milieu. They act as regulators of cell interactions in vertebrates. They are divided into two subfamilies, A and B, according to their overall molecular organisation. The subgroup A proteins TSP-1 and -2 contain an N-terminal domain, a VWFC domain, three TSP1 repeats, three EGF-like domains, TSP3 repeats and a C-terminal domain. They are assembled as trimer. The subgroup B thrombospondins, designated TSP-3, -4, and COMP (cartilage oligomeric matrix protein, also designated TSP-5) are distinct in that they contain unique N-terminal regions, lack the VWFC domain and TSP1 repeats, contain four copies of EGF-like domains, and are assembled as pentamers []. EGF, TSP3 repeats and the C-terminal domain are thus the hallmark of a thrombospondin.This repeat was first described in 1986 by Lawler and Hynes []. It was found in the thrombospondin protein where it is repeated 3 times. Now a number of proteins involved in the complement pathway (properdin, C6, C7, C8A, C8B, C9) []as well as extracellular matrix protein like mindin, F-spondin [], SCO-spondin and even the circumsporozoite surface protein 2 and TRAP proteins of Plasmodium [, ]contain one or more instance of this repeat. It has been involved in cell-cell interaction, inhibition of angiogenesis []and apoptosis [].The intron-exon organisation of the properdin gene confirms the hypothesis that the repeat might have evolved by a process involving exon shuffling []. A study of properdin structure provides some information about the structure of the thrombospondin type I repeat [].
The D-galactoside binding lectin purified from sea urchin (Anthocidaris crassispina) eggs exists as a disulphide-linked homodimer of two subunits; the dimeric form is essential for hemagglutination activity []. The sea urchin egg lectin (SUEL) forms a new class of lectins. Although SUEL was first isolated as a D-galactoside binding lectin, it was latter shown that it bind to L-rhamnose preferentially [, ]. L-rhamnose and D-galactose share the same hydroxyl group orientation at C2 and C4 of the pyranose ring structure.A cysteine-rich domain homologous to the SUEL protein has been identified in the following proteins [, , ]:Plant beta-galactosidases () (lactases).Mammalian latrophilin, the calcium independent receptor of alpha-latrotoxin (CIRL). The galactose-binding lectin domain is not required for alpha-latratoxin binding [].Human lectomedin-1.Rhamnose-binding lectin (SAL) from catfish (Silurus asotus, Namazu) eggs. This protein is composed of three tandem repeat domains homologous to the SUEL lectin domain. All cysteine positions of each domain are completely conserved [].The hypothetical B0457.1, F32A7.3A and F32A7.3B proteins from Caenorhabditis elegans.The human KIAA0821 protein.
The insulin family of proteins groups together several evolutionarily related active peptides []: these include insulin [, ], relaxin [, ], insect prothoracicotropic hormone (bombyxin) [], insulin-like growth factors (IGF1 and IGF2) [, ], mammalian Leydig cell-specific insulin-like peptide (gene INSL3), early placenta insulin-like peptide (ELIP) (gene INSL4), locust insulin-related peptide (LIRP), molluscan insulin-related peptides (MIP), and Caenorhabditis elegans insulin-like peptides. The 3D structures of a number of family members have been determined [, , ]. The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of 4 cysteines in their A chain, the first of which is linked by a disulphide bond to the third, while the second and fourth are linked by interchain disulphide bonds to cysteines in the B chain. Relaxin is encoded by two non-allelic genes in humans and great apes, and by a single gene in all other species studied to date []. The expression of human relaxin genes (H1 and H2) has been characterised in placenta, decidua, prostate and ovary: H2 relaxin mRNA was detected in the ovary, term placenta, decidua, and prostate gland; by contrast, H1 gene expression was detected only in the prostate gland []. Synthesised in the corpora lutea of ovaries during pregnancy, relaxin is released into the blood stream prior to parturition []. With oestrogen, it acts to produce dilation of the birth canal in many mammals, its major biological role being to remodel the reproductive tract to facilitate the birth process [].
These proteins are members of the wider radical SAM superfamily of enzymes that enzymes utilise an iron-sulphur redox cluster and S-adenosylmethionine to carry out diverse radical mediated reactions []. The Acidithiobacillus ferrooxidans ATCC 23270 protein (AFE_0975) is encoded in the same locus as the genes for squalene-hopene cyclase (SHC, ) and other proteins associated with the biosynthesis of hopanoid natural products. Similarly, in Ralstonia eutropha (strain JMP134) (Alcaligenes eutrophus) (Reut_B4901) this protein is encoded adjacent to the genes for HpnAB, IspH and HpnH (), although SHC itself is elsewhere in the genome. Notably, this protein (here named HpnJ) and three others form a conserved set (HpnIJKL) which occur in a subset of all genomes containing the SHC enzyme. This relationship was discerned using the method of partial phylogenetic profiling []. This group includes Zymomonas mobilis the organism where the initial hopanoid biosynthesis locus was described consisting of the genes HpnA-E and SHC (HpnF) []. Continuing past SHC are genes encoding a phosphorylase enzyme (ZMO0873, i.e. HpnG, ) and another radical SAM enzyme (ZMO0874), HpnH. Although discontinuous in Z. mobilis, we continue the gene symbol sequence with HpnIJKL. One of the well-described hopanoid intermediates is bacteriohopanetetrol. In the conversion from hopene several reactions must occur in the side chain for which a radical mechanism might be reasonable. These include the four (presumably anaerobic) hydroxylations and a methyl shift.
This domain is found in betacoronavirus non-structural protein NSP3, and is about 65 amino acids in length. It was originally thought to exist only in SARS-coronaviruses, and so was termed the SARS-unique domain (SUD), however this has since been shown to be incorrect. The domain is also known as DPUP (domain preceding Ubl2 and PL2pro).NSP3 is the product of ORF1a and proteolytically released from the pp1a/1ab polyprotein [, ]. The SUD domain has three globular domains, SUD-N (N-terminal), SUD-M (middle region of SUD), and SUD-C (C-terminal). SUD-C adopts a fold consisting of seven β-strands arranged in an anti-parallel β-sheet, and two α-helices which are packed against the same side of the β-sheet. It adopts a frataxin like fold with structural similarities to DNA-binding domains. It has been shown that SUD-C binds to single-stranded RNA and recognises purine bases more strongly than pyrimidine bases, but these interactions are stabilised in the presence of SUD-M. The function of this domain is not clear but studies of structural homologues of SUD-C suggest that it could be related to metal, adenylate and nucleic acid binding [].
Enzymes containing the cyclodeaminase domain function in channelling one-carbon units to the folate pool. In most cases, this domain catalyses the cyclisation of formimidoyltetrahydrofolate to methenyltetrahydrofolate as shown in reaction (1). In the methylotrophic bacterium Methylobacterium extorquens, however, it catalyses the interconversion of formyltetrahydrofolate and methylenetetrahydrofolate [],as shown in reaction (2)(1) 5-formimidoyltetrahydrofolate = 5,10-methenyltetrahydrofolate + NH(3)(2) 10- formyltetrahydrofolate = 5,10-methenyltetrahydrofolate + H(2)OIn prokaryotes, this domain mostly occurs on its own, while in eukaryotes it is fused to a glutamate formiminotransferase domain (which catalyses the previous step in the pathway) to form the bifunctional enzyme formiminotransferase-cyclodeaminase []. The eukaryotic enzyme is a circular tetramer of homodimers [], while the prokaryotic enzyme is a dimer [, ].The crystal structure of the cyclodeaminase enzyme () from Thermaotoga maritima has been studied []. It is a homodimer, where each monomer is composed of six alpha helices arranged in an up and down helical bundle, forming a novel fold. The location of the active site is not known, but sequence alignments revealed two clusters of conserved residues located in a deep pocket within the dimmer interface. This pocket was large enough to accommodate the reaction product and it was postulated that this is the active site.
This entry contains Escherichia coli (strain K12) YfbR. It is a 5'-deoxynucleotidase that functions as a dCMP phosphohydrolase in a salvage pathway for the synthesis of dUMP in a dcd/deoA mutant []. YfbR contains a conserved HD domain []. YfbR has phosphatase activity with deoxyribonucleoside 5'-monophosphates and does not hydrolyze ribonucleotides or deoxyribonucloside 3'-monophosphates []. Nucleotidase activity of YfbR was discovered in a high-throughput screen of purified proteins []. Crystal structures of YfbR have been solved; based on an analysis of crystal packing and size-exclusion chromatography, it was suggested that the biological unit is a dimer. Site-directed mutagenesis confirmed the importance of certain conserved active site residues, and mechanisms for substrate selectivity and catalysis were proposed [].This family also includes phage HD domain-containing hydrolase-like enzymes, such as A0A2H5BHG9 and A0A2L0V156 from Acinetobacter phage SH-Ab 15497 [], which are associated with PurZ, an enzyme that catalyses the synthesis of diaminopurine (Z), a DNA modification that gives phages an advantage for evading host restriction enzymes activity. They have 2'-deoxyadenine 5'-triphosphate triphosphohydrolase (dATPase) activity, and catalyse the hydrolysis of 2'-deoxyadenine 5'-triphosphate (dATP) to 2'-deoxyadenine (dA) and triphosphate, with the highest activity using Co2+ as the divalent metal cofactor. These enzymes are highly specific for dATP and also catalyse the hydrolysis of dADP and dAMP into dA, releasing pyrophosphate and phosphate, respectively. Thus, these dATPases facilitate the synthesis of Z-genome synthesis removing dATP and dADP from the nucleotide pool of the host [].
The HBM sensor domain has been identified primarily in bacterial chemoreceptors but is also present on histidine kinases. Characteristic features of this domain are its size of approximately 250 amino acids and its location in the bacterial periplasm []. The McpS chemoreceptor of Pseudomonas putida KT2440 was found to possess an HBM sensor domain and its 3D structure in complex with physiologically relevant ligands has been reported []. This domain is composed of 2 long and 4 short helices that form two modules each composed of a 4-helix bundle. The McpS chemoreceptor mediates chemotaxis towards a number of organic acids [, ]. Both modules of the McpS HBM domain contain a ligand binding site. Chemo-attractants binds to each of these sites and their binding was shown to trigger a chemotactic response []. This domain is primarily found in different proteobacteria but also in archaea. Interestingly, amino acids in both ligand binding sites showed a high degree of conservation suggesting that members of this family sense similar ligands.
This entry represents the PX domain found in Sorting nexin-6 (SNX6).SNX6 was found to interact with members of the transforming growth factor-beta family of receptor serine/threonine kinases. Strong heteromeric interactions were also seen among SNX1, -2, -4, and -6, suggesting the formation in vivoof oligomeric complexes. SNX6 is localized in the cytoplasm where it is thought to target proteins to the trans-Golgi network []. In addition, SNX6 was found to be translocated from the cytoplasm to nucleus by Pim-1, an oncogene product of serine/threonine kinase. This translocation is not affected by Pim-1-dependent phosphorylation, but the functional significance is unknown [].The Phox Homology (PX) domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds phosphoinositides (PIs) and targets the protein to PI-enriched membranes [, ]. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway [, , ].
This entry is represented by Coronavirus non-structural protein 2A (32kDa); it is a family of uncharacterised viral proteins.Members have a phosphoesterase module (2H) []and are predicted to be involved in RNA modification. The viral group of 2H phosphoesterases contains proteins from two unrelated virus types: the type C rotaviruses (VP3 protein, ) that are double stranded multipartite RNA viruses and the coronaviruses (NS2 protein, this group) that are positive strand RNA viruses. Given that these viruses have vertebrate hosts, it is likely that the 2H phosphoesterase domain was derived from the host by one of virus groups followed by rapid sequence divergence []. Subsequently, it may have been exchanged between the viral families. Although the direction of the exchange is not clear, it is possible that a double stranded replicative form of a subgenomic RNA transcript of the coronavirus NS2 was stabilised by a rotavirus and incorporated into its multiple double stranded RNA genome []. These proteins can be utilised as novel drug targets because of their predicted RNA modification role.
Proteins in this entry contain glycosyl transferase family 2 domains which are responsible, generally, for the transfer of nucleotide-diphosphate sugars to substrates such as polysaccharides and lipids. The Acidithiobacillus ferrooxidans ATCC 23270 protein (AFE_0974) is encoded in the same locus as the genes for squalene-hopene cyclase (SHC, ) and other proteins associated with the biosynthesis of hopanoid natural products. Similarly, in Ralstonia eutropha (strain JMP134) (Alcaligenes eutrophus) this protein (Reut_B4902) is encoded adjacent to the genes for HpnAB, IspH and HpnH (), although SHC itself is encoded elsewhere in the genome. Notably, this protein (here named HpnI) and three others form a conserved set (HpnIJKL) which occurs in a subset of all genomes containing the SHC enzyme. This relationship was discerned using the method of partial phylogenetic profiling []. This group includes Zymomonas mobilis, the organism where the initial hopanoid biosynthesis locus was described consisting of the genes HpnA-E and SHC (HpnF) []. Continuing past SHC are found genes for a phosphorylase enzyme (ZMO0873, i.e. HpnG, ) and another radical SAM enzyme (ZMO0874), HpnH. Although discontinuous in Z. mobilis, we continue the gene symbol sequence with HpnIJKL. Hopanoids are known to feature polar glycosyl head groups in many organisms.
The polyamines putrescine, spermidine and spermine represent a group of naturally occurring compounds exerting a bewildering number of biological effects. Their biosynthesis is accomplished by a concerted action of four different enzymes: ornithine decarboxylase, adenosylmethionine decarboxylase, spermidine synthase and spermine synthase. The development and introduction of specific inhibitors to the biosynthetic enzymes of the polyamines have revealed that an undisturbed synthesis of the polyamines is a prerequisite for animal cell proliferation to occur []. The human spermine synthase gene is involved in polyamine metabolism and is localised to the Xp22 region []. From isolated and sequenced cDNA clones that encode human spermine synthase , it was found the total length of the sequenced cDNA was 1,612 nucleotides, containing an open reading frame encoding a polypeptide chain of 368 amino acids. All other sequenced peptide fragments of human and bovine spermine synthase proteins could be located within the coding region derived from the cDNA. Sequence comparisons between human spermine synthase and spermidine synthases from bacterial and mammalian sources revealed a nearly complete lack of similarity between the primary structures of these two enzymes catalyzing almost identical reactions indicating they could haveevolved separately [].
Claudins form the paracellular tight junction seal in epithelial tissues. In humans, 24 claudins (claudin 1-24) have been identified. Their ability to polymerise and form strands is affected by the cell types [, , ]. They can also form heteropolymers with each other within and between tight junction strands []. Most of the claudins (claudin-12 being the exception) have a C-terminal PDZ-binding motif that can interact with other PDZ domain proteins, such as scaffolding protein, ZO-1, -2 and -3 []. They also interact with non-tight junction proteins, such as cell adhesion proteins EpCam and tetraspanins and the signaling proteins, ephrin A and B and their receptors, EphA and EphB [].Claudin-11 was originally termed oligodendrocyte-specific protein (OSP).It was reclassified as claudin-11 due to its sequence similarity to claudins and its ability to form TJ strands in transfected fibroblasts.Claudin-11 expression is highly regulated during development and it has been postulated that it may play an important role in the growth and differentiation of oligodendrocytes and other cells outside the CNS [].
Claudins form the paracellular tight junction seal in epithelial tissues. In humans, 24 claudins (claudin 1-24) have been identified. Their ability to polymerise and form strands is affected by the cell types [, , ]. They can also form heteropolymers with each other within and between tight junction strands []. Most of the claudins (claudin-12 being the exception) have a C-terminal PDZ-binding motif that can interact with other PDZ domain proteins, such as scaffolding protein, ZO-1, -2 and -3 []. They also interact with non-tight junction proteins, such as cell adhesion proteins EpCam and tetraspanins and the signaling proteins, ephrin A and B and their receptors, EphA and EphB [].Claudin-5 was originally termed lung-specific membrane protein, brainendothelial cell clone 1 protein (BEC1), and transmembrane protein deletedin velo-cardio-facial syndrome (TMVCF). It was reclassified as claudin-5on the basis of cDNA sequence similarity with claudins-1 and -2, and antibody studies that showed it to be expressed at tight junctions []. Claudin-5 may play an important role in development, since the gene is frequently deleted in velo-cardio-facial/DiGeorge syndrome patients [].
The small heat shock proteins of vertebrates are thought to play a major role in the cellular response to stress, and appear to play a role in a range of other physiological activities. Indeed, in response to many forms of stress, including heat, the expression of heat shock proteins is increased, and coincidentally these cells become more stress-resistant. One of these proteins is Heat Shock Protein (hsp) 27, for which 3 hypotheses currently exist to explain its mechanism of action: (i) it has chaperone-like activity, serving as a site where denatured, unfolding proteins can bind until hsp70-dependent refolding can occur; (ii) it stabilises microfilaments, strengthening the cytoskeleton; and (iii) it enhances levels of the cellular antioxidant glutathione []. It was hypothesised that hsp27 associates with different protein partners in order to effect its various cellular functions. Thus, a yeast two-hybrid screen was performed on a rat Sertoli cell cDNA library, which identified a novel binding protein, termed HSPB1-associated protein 1 or Protein Associated with Small Stress protein 1.
Claudins form the paracellular tight junction seal in epithelial tissues. In humans, 24 claudins (claudin 1-24) have been identified. Their ability to polymerise and form strands is affected by the cell types [, , ]. They can also form heteropolymers with each other within and between tight junction strands []. Most of the claudins (claudin-12 being the exception) have a C-terminal PDZ-binding motif that can interact with other PDZ domain proteins, such as scaffolding protein, ZO-1, -2 and -3 []. They also interact with non-tight junction proteins, such as cell adhesion proteins EpCam and tetraspanins and the signaling proteins, ephrin A and B and their receptors, EphA and EphB [].Claudin-16 was originally termed paracellin-1. It was re-classified as claudin-16 on the basis of its sequence similarity to the claudin family[]. Claudin-16 is involved in renal paracellular Mg2+ resorption and is required for selective paracellular conductance []. Defects in the claudin-16 gene are associated with an autosomal recessive chronic interstitial nephritis with diffuse zonal fibrosis (CINF) [, ].
This family represents an alignment of the Zemlya region of closteroviruses. The alignment of the 1a polyprotein of the Closteroviridae family members revealed that this region was not conserved in other genera. The homologs of the Zemlya region are not found in other viral or cellular proteins. This region is named "the Zemlya region"(zemlya)- is the Russian word for "earth", meaning that its conserved amino acid sequence represents a solid ground within the highly variable central region of 1a polyporotein. It is composed of four predicted α-helices, alphaA to alphaD, and contains three conserved positions: i) a strictly conserved glutamate (E) in helix alphaA (E1291 in Beet yellows closterovirus (BYV)); ii) a strictly conserved proline (P1380) in alphaD; and iii) a conserved basic position (arginine or lysine; R1384 in BYV). The presence of a conserved proline in helix alphaD is noteworthy because prolines are strongly disfavoured in helices; this proline most probably induces a kink in the helix. Functional studies have suggested that most part of the Zemlya region, targets the ER and remodels the ER membranes. More specifically, deletion analysis and substitutions of the conserved hydrophobic amino acid residues suggest a role of the putative amphipathic helix1368-1385 (alphaD) in the formation of globules. Hence it was proposed that this specific region in 1a protein protein may be involved in the biogenesis of closterovirus [].
Megakaryocytes are large cells found in the bone marrow that, uponmaturation, fragment into platelets. The term thrombopoietin (TPO) wascoined in 1958 to describe a possible humoral entity that stimulatesmegakaryocyte development into platelets. The discovery of a novelhaemopoietic cytokine receptor encoded by the proto-oncogene c-mpl raisedspeculation that this was the receptor for thrombopoietin, and prompted asearch for the endogenous ligand []. The ligand was cloned and in vivo-administration of the recombinant protein to mice produced a 4-fold increasein circulating platelets. These results suggested that the c-mpl ligand wasin fact thrombopoietin [].More recent studies have shown that TPO is expressed in hepatocytes, therenal proximal tubules, muscle cells and stromal cells in haemopoieticorgans []. TPO is a 332-residue protein with a 2-domain structure. Thedomain at the N terminus is 153 amino acids long, shares similarity witherythropoietin and can itself stimulate megakaryopoiesis in vitro. A four-α-helical structure is predicted, which is typical of many haemopoieticregulators. The C-terminal domain is 179 amino acids long, is highly variable across species and is not required for the binding of c-mpl [].
This domain is found in a family of proteins present widely across bacteria. This family was named initially with reference to the Escherichia coli radC102 mutation which suggested that RadC was involved in repair of DNA lesions []. However, the relevant mutation has subsequently been shown to be in recG, where radC is in fact an allele of recG []. In addition, all attempts to characterise a radiation-related function for RadC in Streptococcus pneumoniae failed, suggesting that it is not involved in repair of DNA lesions, in recombination during transformation, in gene conversion, nor in mismatch repair [].The RadC-like domain belongs to the JAB superfamily of metalloproteins []. The domain shows fusions to an N-terminal Helix-hairpin-Helix (HhH) domain in most instances. Other domain combinations include fusions to the anti-restriction module ArdC, the DinG/RAD3-like superfamily II helicases and the DNAG-like primase. In some bacteria, closely related DinG/Rad3- like superfamily II helicases are fused to a 3'-5' exonuclease in the same position as the RadC-like JAB domain. These conserved domain associations lead to the hypothesis that the RadC-like JAB domains might function as a nuclease [].
Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, is an essential cofactor for nearly 60 Escherichia coli enzymes and 140 human enzymes. It is a highly reactive molecule that is toxic in its free form. The E. coli PROSC, known as yggS, binds to PLP and is involved in PLP homeostasis, supplying this cofactor to apoenzymes while minimizing any toxic side reactions [, ]. Proteins in this entry occur in archaea, bacteria and eukaryotes. The bacterial proteins are co-transcribed with proline biosysnthesis genes, hence this group of proteins are also named the proline synthetase co-transcribed homologues (PROSC) [].The structure of the yeast protein () has been determined to a resolution of 2.0 A []. Similar in structure to the N-terminal domains of alanine racemase and ornithine decarboxylase, it forms a TIM barrel fold which begins with a long N-terminal helix, rather than the classical beta strand found at the beginning of most other TIM barrels. Unlike alanine racemase and ornithine decarboxylase, which are two-domain dimeric proteins, the yeast protein is a single domain monomer. A pyridoxal 5'-phosphate cofactor is covalently bound towards the C-terminal end of the barrel, which is the usual active site in TIM-barrel folds. Some racemase activity was observed for this protein and it was suggested by the authors that it may function as a general racemase [].
Mycoplasma species are unique amongst bacteria in having very small genomesand lacking cell walls, and are wholly dependent on their host for survival,be it in a symbiotic or pathogenic lifestyle []. Some virulent species canquickly adapt to new environments, and utilise a number of cell surfacemoieties to attach to target cells. Although the most common form ofMycoplasma pathogenesis is respiratory infection, some strains have alsobeen implicated in bacterial vaginosis and rheumatoid arthritis [].An outer membrane lipoprotein, designated P48 on account of its 48kDa molecular weight, was purified from Mycoplasma agalactiae []. It was foundto be a potent differentiation/activation factor of human monocytes, and possesses both immunomodulatory and haematopoietic differentiation activities [, ]. This is believed to aid the bacterium by recruiting humanblood cells to the point of infection, and altering them to allow intracellular invasion by Mycoplasma []. Similar species also use theP48 lipoprotein to invade host cells of sheep and cattle, causing contagious agalactia [].Recently, recombinant studies on the Mycoplasma agalactiaeP48 major surface proteinhave shown that changing key elements at the genetic level decreases the immunomodulatory effects of the gene product []. This may lead to a novel vaccine for Mycoplasma infections.
Mutations in the mitochondrial CLU proteins have been shown to result in clustered mitochondria [, , ]. CLU proteins include Saccharomyces cerevisiae clustered mitochondria protein (Clu1p, alias translation initiation factor 31/TIF31p), Dictyostelium discoideum clustered mitochondria protein homologue (CluA), Caenorhabditis elegans clustered mitochondria protein homologue (CLUH/ Protein KIAA0664), Drosophila clueless (alias clustered mitochondria protein homologue), Arabidopsis clustered mitochondria protein (CLU, alias friendly mitochondria protein/FMT), and human clustered mitochondria protein homologue (CLUH).Dictyostelium CluA is involved in mitochondrial dynamics and is necessary for both, mitochondrial fission and fusion []. Drosophila clueless is essential for cytoplasmic localization and function of cellular mitochondria []. The Drosophila clu gene interacts genetically with parkin (park, the Drosophila ortholog of a human gene responsible for many familial cases of Parkinson's disease) []. Arabidopsis CLU/FMT is required for correct mitochondrial distribution and morphology []. The specific role CLU proteins play in mitochondrial processes in not yet known. In an early study, S. cerevisiae Clu1/TIF31p was reported as sometimes being associated with the elF3 translation initiation factor. The authors noted, however, that its tentative assignment as a subunit of elf3 was uncertain, and to date there has been no direct evidence for a role of this protein in translation [].This entry represents a central domain in CLU proteins.
This entry represents the first and second LOTUS domains of MARF1. This domain provides RNA-binding properties to this protein, acting as an adapter to recruit targets for the effector domain NYN at the N-terminal (RNase activity) [].Meiosis regulator and mRNA stability factor 1 (also known as meiosis arrest female protein 1, MARF1, or Limkain-b1) was first identified as a novel peroxisomal autoantigen that co-localizes with a subset of cytoplasmic microbodies marked by ABCD3 []. Later, it was found that it is an essential regulator of oogenesis required for female meiotic progression and retrotransposon surveillance, therefore, involved in the maintenance of genomic integrity. It acts as a RNAse that efficiently cleaves ssRNAs and down-regulates RNA transcripts, either at transcriptional of post-transcriptional level [, ]. It may function both as an adaptor to recruit specific RNA targets and an effector to catalyse the specific cleavages of target RNAs. MARF1 consists of three major domains, the N-terminal NYN domain, two RNA recognition motifs (RRMs) and a C-terminal repeat of LOTUS (also known as OST-HTH) domains.
The seven in absentia (sina) gene was first identified in Drosophila. The Drosophila Sina protein is essential for the determination of the R7 pathway in photoreceptor cell development: the loss of functional Sina results in the transformation of the R7 precursor cell to a non-neuronal cell type. The Sina protein contains an N-terminal RING finger domain C3HC4-type. Through this domain, Sina binds E2 ubiquitin-conjugating enzymes (UbcD1) Sina also interacts with Tramtrack (TTK88) via PHYL. Tramtrack is a transcriptional repressor that blocks photoreceptor determination, while PHYL down-regulates the activity of TTK88. In turn, the activity of PHYL requires the activation of the Sevenless receptor tyrosine kinase, a process essential for R7 determination. It is thought that Sina targets TTK88 for degradation, therefore promoting the R7 pathway. Murine and human homologues of Sina have also been identified. The human homologue Siah-1 []also binds E2 enzymes (UbcH5) and through a series of physical interactions, targets beta-catenin for ubiquitin degradation. Siah-1expression is enhanced by p53, itself promoted by DNA damage. Thus this pathway links DNA damage to beta-catenin degradation [, ]. Sina proteins, therefore, physically interact with a variety of proteins. The N-terminal RING finger domain that binds ubiquitin conjugating enzymes is a C3HC4-type, and does not form part of the alignment for this family. The remainder C-terminal part is involved in interactions with other proteins, and is included in this alignment. In addition to the Drosophila protein and mammalian homologues, whose similarity was noted previously, this family also includes putative homologues from Caenorhabditis elegans, Arabidopsis thaliana.
Mammalian translationally controlled tumour protein (TCTP) (or P23) is a protein which has been found to be preferentially synthesised in cells during the early growth phase of some types of tumour [, ], but which is also expressed in normal cells. The physiological function of TCTP is still not known. It was first identified as a histamine-releasing factor, acting in IgE +-dependent allergic reactions. In addition, TCTP has been shown to bind to tubulin in the cytoskeleton, has a high affinity for calcium, is the binding target for the antimalarial compound artemisinin, and is induced in vitamin D-dependent apoptosis. TCTP production is thought to be controlled at the translational as well as the transcriptional level []. TCTP is a hydrophilic protein of 18 to 20 kD. TCTPs do not share significant sequence similarity with any other class of proteins. Recently, the structure of TCTP was determined and exhibited significant structural similarity to the human protein Mss4, which is a guanine nucleotide-free chaperone of the Rab protein []. Close homologues have been found in plants [], earthworm [], Caenorhabditis elegans (F52H2.11), Hydra, Saccharomyces cerevisiae (YKL056c) []and Schizosaccharomyces pombe (SpAC1F12.02c).
The D-galactoside binding lectin purified from sea urchin (Anthocidaris crassispina) eggs exists as a disulphide-linked homodimer of two subunits; the dimeric form is essential for hemagglutination activity []. The sea urchin egg lectin (SUEL) forms a new class of lectins. Although SUEL was first isolated as a D-galactoside binding lectin, it was latter shown that it bind to L-rhamnose preferentially [, ]. L-rhamnose and D-galactose share the same hydroxyl group orientation at C2 and C4 of the pyranose ring structure.A cysteine-rich domain homologous to the SUEL protein has been identified in the following proteins [, , ]:Plant beta-galactosidases () (lactases).Mammalian latrophilin, the calcium independent receptor of alpha-latrotoxin (CIRL). The galactose-binding lectin domain is not required for alpha-latratoxin binding [].Human lectomedin-1.Rhamnose-binding lectin (SAL) from catfish (Silurus asotus, Namazu) eggs. This protein is composed of three tandem repeat domains homologous to the SUEL lectin domain. All cysteine positions of each domain are completely conserved [].The hypothetical B0457.1, F32A7.3A and F32A7.3B proteins from Caenorhabditis elegans.The human KIAA0821 protein.Structurally, the rhamnose-binding lectin domain (also known as the N-terminal lectin domain, Lec) is composed of five β-strands , a single, long α-helix, and two small helical elements. The overall fold is that of a β-sandwich with two antiparallel sheets [].
Neurotransmitter ligand-gated ion channels are transmembrane receptor-ion channel complexes that open transiently upon binding of specific ligands, allowing rapid transmission of signals at chemical synapses [, ]. Five of these ion channel receptor families have been shown to form a sequence-related superfamily:Nicotinic acetylcholine receptor (AchR), an excitatory cation channel in vertebrates and invertebrates; in vertebrate motor endplates it is composed of alpha, beta, gamma and delta/epsilon subunits; in neurons it is composed of alpha and non-alpha (or beta) subunits [].Glycine receptor, an inhibitory chloride ion channel composed of alpha and beta subunits [].Gamma-aminobutyric acid (GABA) receptor, an inhibitory chloride ion channel; at least four types of subunits (alpha, beta, gamma and delta) are known [].Serotonin 5HT3 receptor, of which there are seven major types (5HT3-5HT7) [].Glutamate receptor, an excitatory cation channel of which at least three types have been described (kainate, N-methyl-D-aspartate (NMDA) and quisqualate) [].These receptors possess a pentameric structure (made up of varying subunits), surrounding a central pore. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related. They are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions which form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence [, ].Gamma-aminobutyric acid type A (GABAA) receptors are members of the neurotransmitter ligand-gated ion channels: they mediate neuronal inhibition on binding GABA. The effects of GABA on GABAA receptors are modulated by a range of therapeutically important drugs, including barbiturates, anaesthetics and benzodiazepines (BZs) []. The BZs are a diverse range of compounds, including widely prescribed drugs, such as librium and valium, and their interaction with GABAA receptors provides the most potent pharmacological means of distinguishing different GABAA receptor subtypes.GABAA receptors are pentameric membrane proteins that operate GABA-gated chloride channels []. Eight types of receptor subunit have been cloned, with multiple subtypes within some classes: alpha 1-6, beta 1-4, gamma 1-4, delta, epsilon, pi, rho 1-3 and theta [, ]. Subunits are typically 50-60kDa in size and comprise a long N-terminal extracellular domain, containing a putative signal peptide and a disulphide-bonded beta structural loop; 4 putative transmembrane (TM) domains; and a large cytoplasmic loop connecting the third and fourth TM domains. Amongst family members, the large cytoplasmic loop displays the most divergence in terms of primary structure, the TM domains showing the highest level of sequence conservation [].Most GABAA receptors contain one type of alpha and beta subunit, and a single gamma polypeptide in a ratio of 2:2:1 [], though in some cases other subunits such as epsilon or delta may replace gamma. The BZ binding site is located at the interface of adjacent alpha and gamma subunits; therefore, the type of alpha and gamma subunits present is instrumental in determining BZ selectivity and sensitivity. Receptors can be categorised into 3 groups based on their alpha subunit content and, hence, sensitivity to BZs: alpha 1-containing receptors have greatest sensitivity towards BZs (type I); alpha 2, 3 and 5-containing receptors have similar but distinguishable properties (type II); and alpha 4- and 6-containing assemblies have very low BZ affinity []. A conserved histidine residue in the alpha subunit of type I and II receptors is believed to be responsible for BZ affinity []. Identification and characterisation of the theta subunit was first reportedin 1999 []. Cloning of the full-length cDNA was performed using a humanwhole-brain library, yielding a deduced open reading frame of 627 aminoacids. This polypeptide was found to be most similar to the beta 1 subunitwith regard to sequence identity, and was able to co-assemble with alpha 2,beta 1 and gamma 1 subunits, yielding heteromeric assemblies with a 4-foldincrease in sensitivity towards GABA. Furthermore, theta mRNA was found to have a unique spatial distribution, with significant expression withinmonoaminergic neurons of both human and monkey brain.
O-Glycosyl hydrolases () are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families [, ]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.Glycoside hydrolase family 22 comprises enzymes with two known activities; lysozyme type C () (also known as 1, 4-beta-N-acetylmuramidase or LYZ) and alpha-lactalbumins (also known as lactose synthase B protein or LA). Asp and/or the carbonyl oxygen of the C-2 acetamido group of the substrate acts as the catalytic nucleophile/base. Alpha-lactalbumin [, ]is a milk protein that acts as the regulatory subunit of lactose synthetase, acting to promote the conversion of galactosyltransferase to lactose synthase, which is essential for milk production. In the mammary gland, alpha-lactalbumin changes the substrate specificity of galactosyltransferase from N-acetylglucosamine to glucose.Lysozymes () act as bacteriolytic enzymes by hydrolyzing the beta(1->4) bonds between N-acetylglucosamine and N-acetylmuramic acid in the peptidoglycan of prokaryotic cell walls. It has also been recruited for a digestive role in certain ruminants and colobine monkeys []. There are at least five different classes of lysozymes []: C (chicken type), G (goose type), phage-type (T4), fungi (Chalaropsis), and bacterial (Bacillus subtilis). There are few similarities in the sequences of the different types of lysozymes.Lysozyme type C and alpha-lactalbumin are similar both in terms of primary sequence and structure, and probably evolved from a common ancestral protein []. Around 35 to 40% of the residues are conserved in both proteins as well as the positions of the four disulphide bonds. There is, however, no similarity in function. Another significant difference between the two enzymes is that all lactalbumins have the ability to bind calcium [], while this property is restricted to only a few lysozymes []. The binding site was deduced using high resolution X-ray structure analysis and was shown to consist of three aspartic acid residues. It was first suggested that calcium bound to lactalbumin stabilised the structure, but recently it has been claimed that calcium controls the release of lactalbumin from the golgi membrane and that the pattern of ion binding may also affect the catalytic properties of the lactose synthetase complex.Sperm acrosome membrane-associated protein 3 (SPACA3) is involved in fertilization, probably during the sperm-egg membrane fusion, but despite being homologous to lysosome has no detectable bacteriolytic activity [].
O-Glycosyl hydrolases () are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families [, ]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.Glycoside hydrolase family 22 comprises enzymes with two known activities; lysozyme type C () and alpha-lactalbumins. Asp and/or the carbonyl oxygen of the C-2 acetamido group of the substrate acts as the catalytic nucleophile/base. Alpha-lactalbumin [, ]is a milk protein that acts as the regulatory subunit of lactose synthetase, acting to promote the conversion of galactosyltransferase to lactose synthase, which is essential for milk production. In the mammary gland, alpha-lactalbumin changes the substrate specificity of galactosyltransferase from N-acetylglucosamine to glucose.Lysozymes () act as bacteriolytic enzymes by hydrolyzing the beta(1->4) bonds between N-acetylglucosamine and N-acetylmuramic acid in the peptidoglycan of prokaryotic cell walls. It has also been recruited for a digestive role in certain ruminants and colobine monkeys []. There are at least five different classes of lysozymes []: C (chicken type), G (goose type), phage-type (T4), fungi (Chalaropsis), and bacterial (Bacillus subtilis). There are few similarities in the sequences of the different types of lysozymes.Lysozyme type C and alpha-lactalbumin are similar both in terms of primary sequenceand structure, and probably evolved from a common ancestral protein []. Around 35 to 40% of the residues are conserved in both proteins as well as the positions of the four disulphide bonds. There is, however, no similarity in function. Another significant difference between the two enzymes is that all lactalbumins have the ability to bind calcium [], while this property is restricted to only a few lysozymes []. The binding site was deduced using high resolution X-ray structure analysis and was shown to consist of three aspartic acid residues. It was first suggested that calcium bound to lactalbumin stabilised the structure, but recently it has been claimed that calcium controls the release of lactalbumin from the golgi membrane and that the pattern of ion binding may also affect the catalytic properties of the lactose synthetase complex.This domain includes three cysteines which are involved in two of the disulphide bonds found in these proteins.
This superfamily comprises structural domains found at the N terminus of various ligases from the ANL superfamily. The name ANL derives from three of the subfamilies - Acyl-CoA synthetases, the adenylation domains of the modular non-ribosomal peptide synthetases (NRPSs), and the luciferase enzymes. Members of this superfamily include luciferase, long chain fatty acid Co-A ligase, acetyl-CoA synthetase and various other closely-related synthetases as well as a plant auxin-responsive promoter family. These enzymes are involved in catalysing the initial adenylation of a carboxylate to form an acyl-AMP intermediate, followed by a second partial reaction, most commonly the formation of a thioester. These adenylating enzymes utilise a 140 degrees rotation of the C-terminal domain to adopt two distinct conformations that are used for the adenylation and thiolation reactions. Thus, by using two different conformations of the C-terminal domain, these enzymes perform two distinct steps of catalysis.Luciferases are composed of a large N-terminal domain and a smaller C-terminal domain, which form a cleft. The active site of these enzymes is located at the interface between these two domains, with most active site residues located in the N-terminal domain, and two lysine residues in the C-terminal domain. The N-terminal domain is involved in catalysis, and the C-terminal domain is essential for luciferase activation during the catalytic reaction [, ].The overall structure of the N-terminal domain has been characterised in a fatty acyl-CoA ligase in M. tuberculosis, FA and fatty acyl-AMP ligase FAAL28. The N-terminal domain of FA consists of three subdomains: subdomains A and B form α+β topology, which pack together to form a five-layered α-β-α-β-α tertiary structure. The third subdomain C folds into a distorted β-barrel topology. In FAAL28, the C-subdomain presents an insertion between β-strands 1 and 2. A hydrophobic interaction was identified at the interface of insertion and N-terminal domain, and it was suggested to play a fundamental role in anchoring the insertion motif and arresting the acyl-CoA catalysis [].The Mycobacterium tuberculosis fatty acyl-CoA synthetase (ACS) FadD13 is a peripheral membrane protein essential for virulence and intracellular growth of the pathogen. FadD13 was identified to play a central role in lipid metabolism, and therefore would be a possible drug target. FadD13 comprises an N- and a C-terminal domain. The N-terminal domain folds into an α+β topology and can be further divided into two subdomains. The CoA binding site in ACS proteins is formed in the junction between the domains upon a 140 degrees rotation of the C-terminal domain after the initial adenylation step [, ].
TMEPAI was originally identified as a highly androgen-induced gene by serial analysis of gene expression in androgen-treated LNCaP prostate cancer (CaP) cells []. It is a type I transmembrane protein that has an N-erminal extracellular and a single transmembrane domains. TMEPAI contains two PY motifs that can be targetedby the WW domain. It is involved in a negative feedback loop to control the duration and intensity of TGF-beta signaling, which regulates growth suppression, apoptosis induction, extracellular matrix production, and differentiation []. It is also involved in androgen receptor signalling, phosphatase and tensin homologue deleted on chromosome 10 signalling, and formation of autophagosomes in addition to degradation of TbetaRI (TGF-beta type I receptor) through lysosomes []. TMEPAI has been linked to cancers [, , ].
Type VI secretion system (T6SS) appears to be confined to Proteobacteria. It is important for bacterial pathogenesis, but it is also found in non-pathogenic bacteria, suggesting that T6SS involvement is not limited to virulence []. T6SS was identified in Vibrio cholerae []and Pseudomonas aeruginosa [], and exports Hcp (Haemolysin-Coregulated Protein) and a class of proteins named Vgr (Val-Gly Repeats). In addition to Vgr and Hcp proteins, T6SS is characterised by the presence of an AAA+ Clp-like ATPase and of two additional genes icmF and dotU, encoding homologues of T4SS stabilising proteins []. This entry represent the Vgr family of proteins, associated with some classes of Rhs elements (Rhs classes G and E). Rsh (rearrangement hot-spot) elements are repetitious sequences identified in certain Escherichia coli strains [, ].
These sequences represent a family of proteins from the malaria parasite Plasmodium falciparum, several of which have been shown to be expressed specifically in the ring stage as well as the rodent parasite Plasmodium yoelii []. A homologue from Plasmodium chabaudi was localized to the parasitophorous vacuole membrane []. Members have an initial hydrophobic, Phe/Tyr-rich stretch long enough to span the membrane, a highly charged region rich in Lys, a second putative transmembrane region, and a second highly charged, low complexity sequence region. Some members have up to 100 residues of additional C-terminal sequence. These genes have been shown to be found in the sub-telomeric regions of both Plasmodium falciparum and P. yoelii chromosomes.
The short-chain dehydrogenases/reductases family (SDR) [, ]is a very large family of enzymes, most of which are known to be NAD- or NADP-dependent oxidoreductases. As the first member of this family to be characterised was Drosophila alcohol dehydrogenase, this family used to be called [, , ]'insect-type', or 'short-chain' alcohol dehydrogenases. Most members of this family are proteins of about 250 to 300 amino acid residues. Most dehydrogenases possess at least 2 domains [], the first binding the coenzyme, often NAD, and the second binding the substrate. This latter domain determines the substrate specificity and contains amino acids involved in catalysis. Little sequence similarity has been found in the coenzyme binding domain although there is a large degree of structural similarity, and it has therefore been suggested that the structure of dehydrogenases has arisen through gene fusion of a common ancestral coenzyme nucleotide sequence with various substrate specific domains [].
Shikimate kinase () catalyses the fifth step in the biosynthesis of aromatic amino acids from chorismate (the so-called shikimate pathway) []. The enzyme catalyses the following reaction:ATP + shikimate = ADP + shikimate-3-phosphateThe protein is found in bacteria (gene aroK or aroL), plants and fungi (whereit is part of a multifunctional enzyme that catalyses five consecutive steps in this pathway). In 1994, the 3D structure of shikimate kinase was predicted to be very close to that of adenylate kinase, suggesting a functional similarity as well as an evolutionary relationship []. This prediction has since been confirmed experimentally. The protein is reported to possess an alpha/beta fold, consisting of a central sheet of five parallel β-strands flanked by α-helices. Such a topology is very similar to that of adenylate kinase [].The N terminus of threonine synthase-like 1 from metazoan shares protein sequence similarity with shikimate kinase and is included in this entry. However, their functions may be different.
Shikimate kinase () catalyses the fifth step in the biosynthesis of aromatic amino acids from chorismate (the so-called shikimate pathway) []. The enzyme catalyses the following reaction:ATP + shikimate = ADP + shikimate-3-phosphateThe protein is found in bacteria (gene aroK or aroL), plants and fungi (whereit is part of a multifunctional enzyme that catalyses five consecutive steps in this pathway). In 1994, the 3D structure of shikimate kinase was predicted to be very close to that of adenylate kinase, suggesting a functional similarity as well as an evolutionary relationship []. This prediction has since been confirmed experimentally. The protein is reported to possess an alpha/beta fold, consisting of a central sheet of five parallel β-strands flanked by α-helices. Such a topology is very similar to that of adenylate kinase [].The N terminus of threonine synthase-like 1 from metazoan shares protein sequence similarity with shikimate kinase and is included in this entry. However, their functions may be different.
Members of this family show a broad specificity for prenyl diphosphates, accepting substrates of different chain lengths. Genes coding for these enzymes have been identified in many organisms, and are mostly responsible for ubiquinone (UQ) biosynthesis [, , ]. 4-hydroxybenzoate solanesyltransferase from cyanobacteria displays a broad specificity with regard to the prenyl donor substrate and uses not only solanesyl diphosphate, but also a number of shorter-chain prenyl diphosphates []. One exception is LePGT1 (Lithospermum erythrorhizon 4-hydroxybenzoic acid geranyltransferase), which only accepts GPP (geranyl diphosphate) and is involved in the biosynthesis of a red naphthoquinone, shikonin, a plant secondary metabolite []. LePGT1 was reported to be the key regulatory enzyme of shikonin biosynthesis []and is not relevant to the formation of UQ [].
This entry represents the 35-36 amino acid motif known as the R&R consensus. This is a conserved region found in insect cuticular proteins []. Insect cuticle is composed of proteins and chitin. The cuticular proteins seem to be specific to the type of cuticle (flexible or stiff) that occur at stages of the insect development. The proteins found in the flexible cuticle of larva and pupa of different insects share a conserved C-terminal section []; such a region is also found in the soft endocuticle of adults insects []as well as in other cuticular proteins including in arachnids []. This conserved motifof 35-36 amino acids is known as the R&R consensus since it was firstrecognised by Rebers and Riddiford. N-terminal to the consensus is a region ofhydrophilic amino acids. The two regions together have been called theextended R&R consensus, and form an approximately 70 amino acids chitin-binding domain[, ].
This family is a small group of metazoan sequences with sequences from Arabidopsis thaliana (Mouse-ear cress) and rice. The sequences represent pyrimidine 5-nucleotidases, apparently in reference to HSPC233, the Homo sapiens (Human) homologue []. The structure of mouse sequence has been reported []. This group of sequences was originally found during searches for members of the haloacid dehalogenase (HAD) superfamily. All of the conserved catalytic motifs []are found. The placement of the variable domain between motifs 1 and 2 indicates membership in subfamily I of the superfamily, but these sequences are sufficiently different from any of the branches of that subfamily (IA-ID) as to constitute a separate branch to now be called IE. Considering that the closest identifiable hit outside of the noise range is to a phosphoserine phosphatase, this group may be considered to be most closely allied to subfamily IB.
The transport of peptides into cells is a well-documented biological phenomenon which is accomplished by specific, energy-dependent transporters found in a number of organisms as diverse as bacteria and humans. The PTR family of proteins is distinct from the ABC-type peptide transporters and was uncovered by sequence analyses of a number of recently discovered peptide transport proteins []. These proteins that seem to be mainly involved in the intake of small peptides with the concomitant uptake of a proton [].These integral membrane proteins are predicted to comprise twelvetransmembrane regions.This entry describes two conserved sites. The first conserved site is found within a region that includes the end of the second transmembrane region, a cytoplasmic loop as well as the third transmembrane region. The second conserved site corresponds to the core of the fifth transmembrane region.
Crescentin (CreS) is a bacterial equivalent to Intermediate Filament (IF) proteins from eukaryotes. Its cytoskeletal function is required for the vibrioid and helical shapes of Caulobacter crescentus [, ]in which it was seen that without CreS, the cells adopt a straight-rod morphology. CreS, similarly to IF proteins, can assemble itself into filaments in vitro, with no need of energy or additional cofactors. In vivo, CreS forms a helical structure that colocalises with the inner cell curvatures beneath the cytoplasmic membrane []. CreS possesses the typical tripartite IF-like domain architecture found in IF proteins, which contains a coiled-coil rod domain interrupted by linker sequences and short head (N-terminal) and tail (C-terminal) domains [].This entry represents the coiled-coil region of crescentin found in alphaproteobacteria.
This entry consists of the C-terminal region of several eukaryotic and archaeal RuvB-like 1 (Pontin or TIP49a) and RuvB-like 2 (Reptin or TIP49b) proteins. In zebrafish, the liebeskummer (lik) mutation, causes development of hyperplastic embryonic hearts. lik encodes Reptin, a component of a DNA-stimulated ATPase complex. Beta-catenin and Pontin, a DNA-stimulated ATPase that is often part of complexes with Reptin, are in the same genetic pathways. The Reptin/Pontin ratio serves to regulate heart growth during development, at least in part via the beta-catenin pathway []. TBP-interacting protein 49 (TIP49) was originally identified as a TBP-binding protein, and two related proteins are encoded by individual genes, tip49a and b. Although the function of this gene family has not been elucidated, they are supposed to play a critical role in nuclear events because they interact with various kinds of nuclear factors and have DNA helicase activities. TIP49a has been suggested to act as an autoantigen in some patients with autoimmune diseases [].
