This entry represents a group of tetratricopeptide thioredoxin-like proteins (TTLs), including TTL1-4 from Arabidopsis. They are characterised by the presence of six tetratricopeptide repeats in conserved positions and a C-terminal region known as the thioredoxin-like domain with homology to thioredoxins. TTL2 is specific to pollen grains, while TTL1/3/4 display ubiquitous expression in normal growing conditions but differential expression patterns in response to osmotic and NaCl stresses. TTL1, TTL3, and TTL4 have partially overlapping yet specific functions in abiotic stress tolerance while TTL2 is involved in male gametophytic transmission [].
This is a family of uncharacterised tetratricopeptide repeat (TPR) proteins invariably found in heme biosynthesis gene clusters. The absence of any invariant residues other than Ala argues against this protein serving as an enzyme per se. The gene symbol hemY assigned in E. coli is unfortunate in that an unrelated protein, protoporphyrinogen oxidase (HemG in E. coli) is designated HemY in Bacillus subtilis.
This is one of two constant domains forming the CATRA module which is in turn C-terminally fused to a diverse range of conflict effector domains. This gene, along with a gene encoding the CATASP domain and a gene encoding a TPR repeat region fused to a CASPASE domain, forms the three gene island making up the CATRA conflict systems. This all α-helical domain is predicted to be involved in recognition of invasive molecules or in the transmitting of a signal through conformational change, enabling CASPASE-mediated proteolysis to free the fused effector domains [].
This is one of two constant domains forming the CATRA module which is in turn C-terminally fused to a diverse range of conflict effector domains. This gene, along with a gene encoding the CATASP domain and a gene encoding a TPR repeat region fused to a CASPASE domain, forms the three gene island making up the CATRA conflict systems. This α/β domain is predicted to be involved in recognition of invasive molecules or in the transmitting of a signal through conformational change, enabling CASPASE-mediated proteolysis to free the fused effector domains [].
The bacterial PIcR helix-turn-helix transcription factor includes five TPR units of different lengths []. This entry represents the central, medium-sized TPR repeat.
The tetratrico peptide repeat region (TPR) is a structural motif present in a wide range of proteins [, , ]. It mediates protein-protein interactions and the assembly of multiprotein complexes []. The TPR motif consists of 3-16 tandem-repeats of 34 amino acids residues, although individual TPR motifs can be dispersed in the protein sequence. Sequence alignment of the TPR domains reveals a consensus sequence defined by a pattern of small and large amino acids. TPR motifs have been identified in various different organisms, ranging from bacteria to humans. Proteins containing TPRs are involved in a variety of biological processes, such as cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis and protein folding.The X-ray structure of a domain containing three TPRs from protein phosphatase 5 revealed that TPR adopts a helix-turn-helix arrangement, with adjacent TPR motifs packing in a parallel fashion, resulting in a spiral of repeating anti-parallel α-helices []. The two helices are denoted helix A and helix B. The packing angle between helix A and helix B is ~24 degrees within a single TPR and generates a right-handed superhelical shape. Helix A interacts with helix B and with helix A' of the next TPR. Two protein surfaces are generated: the inner concave surface is contributed to mainly by residue on helices A, and the other surface presents residues from both helices A and B. This entry represents SHNi-TPR (Sim3-Hif1-NASP interrupted TPR), a sequence that is an interrupted form of TPR repeat [].
The tetratrico peptide repeat region (TPR) is a structural motif present in a wide range of proteins [, , ]. It mediates protein-protein interactions and the assembly of multiprotein complexes []. The TPR motif consists of 3-16 tandem-repeats of 34 amino acids residues, although individual TPR motifs can be dispersed in the protein sequence. Sequence alignment of the TPR domains reveals a consensus sequence defined by a pattern of small and large amino acids. TPR motifs have been identified in various different organisms, ranging from bacteria to humans. Proteins containing TPRs are involved in a variety of biological processes, such as cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis and protein folding.The X-ray structure of a domain containing three TPRs from protein phosphatase 5 revealed that TPR adopts a helix-turn-helix arrangement, with adjacent TPR motifs packing in a parallel fashion, resulting in a spiral of repeating anti-parallel α-helices []. The two helices are denoted helix A and helix B. The packing angle between helix A and helix B is ~24 degrees within a single TPR and generates a right-handed superhelical shape. Helix A interacts with helix B and with helix A' of the next TPR. Two protein surfaces are generated: the inner concave surface is contributed to mainly by residue on helices A, and the other surface presents residues from both helices A and B.
This is the LGN-binding domain (LBD) of the inscuteable homologue protein. It interacts with the TPR motifs of G-protein-signaling modulator 2 (GPSM2, also known as LGN) and stabilises LGN [].
This is N-terminal tetratricopeptide repeat (TPR) domain found in CHIP, the C terminus of Hsp70 interacting proteins. The TPR domain of CHIP binds directly to EEVD motifs located at the C termini of Hsc/Hsp70 and Hsp90 [].
This is the LGN-binding domain (LBD) of the inscuteable homologue protein. It interacts with the TPR motifs of G-protein-signaling modulator 2 (GPSM2, also known as LGN) and stabilises LGN [].
This family of proteins is functionally uncharacterised. This family of proteins is found in bacteria, mainly Actinobacteria and Firmicutes. Many members are thought to contain TPR regions. There are two conserved motifs, AxRL and LxxY.
This TPR repeat-containing protein is the CcmI protein (also called CycH) of c-type cytochrome biogenesis. CcmI is thought to act as an apo-cytochrome c chaperone. This entry describes the N-terminal region.
The tetratrico peptide repeat (TPR) is a structural motif present in a wide range of proteins [, , ]. It mediates protein-protein interactions and the assembly of multiprotein complexes []. The TPR motif consists of 3-16 tandem-repeats of 34 amino acids residues, although individual TPR motifs can be dispersed in the protein sequence. Sequence alignment of the TPR domains reveals a consensus sequence defined by a pattern of small and large amino acids. TPR motifs have been identified in various different organisms, ranging from bacteria to humans. Proteins containing TPRs are involved in a variety of biological processes, such as cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis and protein folding [].This repeat includes outlying Tetratricopeptide-like repeats (TPR) that are not matched by .
In Gram-positive bacteria, cell-to-cell communication mainly relies on extracellular signaling peptides. ComR is a member of the RNPP family, which positively controls competence for natural DNA transformation in streptococci. It is directly activated by the binding of its associated pheromone XIP []. The crystal structure analysis of ComR shows that it contains an N-terminal helix-turn-helix (HTH), DNA binding domain (DBD) and a C-terminal tetratricopeptide repeat (TPR) domain. The TPR domain is composed of 11 α-helices forming 5 TPR motifs followed by an additional C-terminal α-helix 16 called CAP. The pheromone XIP binding site is found in the TPR region. Biochemical and mutational analysis indicate that, if the interacting XIP is accepted it can then trigger the conformational change of the TPR domain to open the DBD-TPR interface to allow dimer formation that is required to bind DNA [].
The tetratrico peptide repeat (TPR) is a structural motif present in a wide range of proteins [, , ]. It mediates protein-protein interactions and the assembly of multiprotein complexes []. The TPR motif consists of 3-16 tandem-repeats of 34 amino acids residues, although individual TPR motifs can be dispersed in the protein sequence. Sequence alignment of the TPR domains reveals a consensus sequence defined by a pattern of small and large amino acids. TPR motifs have been identified in various different organisms, ranging from bacteria to humans. Proteins containing TPRs are involved in a variety of biological processes, such as cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis and protein folding [].The X-ray structure of a domain containing three TPRs from protein phosphatase 5 revealed thatTPR adopts a helix-turn-helix arrangement, with adjacent TPR motifs packing in a parallelfashion, resulting in a spiral of repeating anti-parallel α-helices []. The two helices are denotedhelix A and helix B. The packing angle between helix A and helix B is ~24 degrees; within asingle TPR and generates a right-handed superhelical shape. Helix A interacts with helix B andwith helix A' of the next TPR. Two protein surfaces are generated: the inner concave surface iscontributed to mainly by residue on helices A, and the other surface presents residues from bothhelices A and B.
This entry includes FKBP6 from mammals and protein shutdown (shu) from flies. FKBP6 is a testis-sperm specific protein that belongs to the immunophilins FKBP family known to be involved in meiosis, calcium homeostasis, clathrin-coated vesicles, and membrane fusions []. FKBP6 contains a PPIase FKBP-type domain and a TPR domain. However, it is inactive as an isomerase and associates with Hsp90 via its TPR domain []. Protein shutdown is essential for the formation of germline cysts during oogenesis []and is a component of the Drosophila piRNA biogenesis machinery [].
The tetratrico peptide repeat region (TPR) is a structural motif present in a wide range of proteins [, , ]. It mediates protein-protein interactions and the assembly of multiprotein complexes []. The TPR motif consists of 3-16 tandem-repeats of 34 amino acids residues, although individual TPR motifs can be dispersed in the protein sequence. Sequence alignment of the TPR domains reveals a consensus sequence defined by a pattern of small and large amino acids. TPR motifs have been identified in various different organisms, ranging from bacteria to humans. Proteins containing TPRs are involved in a variety of biological processes, such as cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis and protein folding.The X-ray structure of a domain containing three TPRs from protein phosphatase 5 revealed that TPR adopts a helix-turn-helix arrangement, with adjacent TPR motifs packing in a parallel fashion, resulting in a spiral of repeating anti-parallel α-helices []. The two helices are denoted helix A and helix B. The packing angle between helix A and helix B is ~24 degrees within a single TPR and generates a right-handed superhelical shape. Helix A interacts with helix B and with helix A' of the next TPR. Two protein surfaces are generated: the inner concave surface is contributed to mainly by residue on helices A, and the other surface presents residues from both helices A and B. The domain represented in this superfamily consists of a multi-helical fold comprised of two curved layers of α-helices arranged in a regular right-handed superhelix, where the repeats that make up this structure are arranged about a common axis []. These superhelical structures present an extensive solvent-accessible surface that is well suited to binding large substrates such as proteins and nucleic acids. The TPR is likely to be an ancient repeat, since it is found in eukaryotes, bacteria and archaea, whereas the PPR repeat is found predominantly in higher plants. The superhelix formed from these repeats can bind ligands at a number of different regions, and has the ability to acquire multiple functional roles [].
S100A1 belongs to the S100 calcium-binding family []. S100A1 plays a critical role in cardiac performance, blood pressure regulation and skeletal muscle function [, ]. S100A1 interacts with protein phosphatase 5 (PP5) via TPR repeats; the interaction is calcium-dependent and modulates PP5 activity [].
BH0479 of Bacillus halodurans is a hypothetical protein which contains a tetratrico peptide repeat (TPR) structural motif. The TPR motif is often involved in mediating protein-protein interactions. This protein is likely to function as a dimer. The first 48 amino acids are not present in the clone construct. This entry represents the tetratricopeptide-like repeats classified as TPR_5 in Pfam.
This entry represents the PEX5-related proteins (PEX5L, also known as TRIP8b) from vertebrates. It acts as an accessory subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, regulating their cell-surface expression and cyclic nucleotide dependence [, ]. Interestingly, although PEX5L and PEX5 have structurally similar binding at their TPR domains, they bind to different substrates in vivo [].
Co-chaperones are helper interacting proteins that modulate the chaperone cycle, being involved in substrate specificity and stimulation of chaperone activity of HSP90/70 and include other heat shock proteins, TPR containing proteins, cyclophilins and others. The TPR containing proteins possess an N-terminal TPR domain, which are more closely related to each other than to TPR domains from other proteins with different functionality [, ], which is involved in HSP90/70 direct interaction. The first N-terminal residues prior to the TRP domain and the C-terminal domain are involved and important for domain interplay and stabilisation of its interactions []. The Hsp90 chaperone machinery in eukaryotes comprises a number of distinct accessory factors, among them TTC4 from human and its homologues Cns1 from yeast and Dpit47 from Drosophila, structurally and functionally conserved from yeast to human. Cns1 is one of the few essential co-chaperones in yeast, important for maintaining translation elongation, specifically chaperoning the elongation factor eEF2. Cns1 interacts with Hgh1 and forms a quaternary complex together with eEF2 and Hsp90 mediating the proper folding and solubility of eEF2. Recently, the C-terminal structure has been solved and is called the "wheel"domain according to its 2D projection. It shows an overall fold consisting of a twisted five-stranded beta sheet surrounded by several alpha helices [].This entry represents the wheel domain found at the C terminus of yeast Cns1, human TTC4 and Drosophila Dpit47 proteins.
Proteins in this entry are designated PilF []and PilW []. This outer membrane protein is required both for pilus stability and for pilus functions such as adherence to human cells. Members of this family contain copies of the TPR (tetratricopeptide repeat) domain.
This entry includes a group TPR repeat-containing proteins, including Sti1 and Tah1 from budding yeasts. Sti1 is a heat shock protein that serves as a Hsp70/90 cochaperone [, ]. It contains one binding site for Hsp90 (TPR2A) and two binding sites for Hsp70 (TPR1 and TPR2B) []. The basic functions of yeast Sti1 and its human homologue, Hop, are conserved [].
This domain is found in a number of proteins, including TPR protein () and yeast myosin-like protein 1 (MLP1, ). These proteins share a number of features; for example, they have coiled-coil regions and are associated with nuclear pores [, , ]. TPR is thought to be a component of nuclear pore complex- attached intranuclear filaments [], and is implicated in nuclear protein import []. Moreover, its N-terminal region is involved in the activation of oncogenic kinases, possibly by mediating the dimerisation of kinase domains or by targeting these kinases to the nuclear pore complex []. Mlp1 acts as a docking platform for for heterogeneous nuclear ribonucleoproteins that are required for mRNA export [].
These eukaryotic serine/threonine phosphoprotein phosphatases, first described from human (PP5) and Saccharomyces cerevisiae (PPT1), are distinguished from related protein phosphatases by an N-terminal region of about 200 residues that contains three tandem tetratricopeptide repeats (TPR) []. Structurally, TPR repeats form a helical scaffold of antiparallel α-helices with an amphipathic groove that mediates protein-protein interactions []. The TPR domains contribute to regulation of PP5 activity, which is normally low but stimulated by interaction with lipid [], and to interaction with other proteins [].PPT1 specifically binds to and dephosphorylates Hsp90 and this dephosphorylation positively regulates the Hsp90 chaperone machinery []. PPP5 is involved in a wide range of processes including apoptosis, differentiation, DNA damage response, cell survival, regulation of ion channels or circadian rhythms, in response hormones, calcium, fatty acids, TGF-beta and also oxidative and genotoxic stresses [, , ].
The Hsc70/Hsp70-interacting protein (Hip, also p48 or suppressor of tumorigenicity ST13) functions as a regulator of the cyclic action of Hsp70. Hip forms homodimers, and this entry represents the N-terminal dimerization domain, which may not be directly involved in its regulatory function. A central domain of Hip that contains TPR repeats binds the ATPase domain of Hsp70 and slows the release of ADP [, , , ].
This is a small, rapidly-evolving domain predicted to possess a compact, four-helix structure. Along with a gene encoding a TPR repeat region fused to a CASPASE domain and a gene encoding the CATRA module (CATRA-N CATRA-C) C-terminally fused to a diverse range of conflict effector domains, forms the three gene island making up the CATRA conflict systems. Plays a possible inhibitory role in theCATRA system which is relieved upon sensing of an invasive molecule or is directly cleaved by the CASPASE domain [].
This entry represents a sensor domain consisting of 7 TPR repeats forming a tightly-wound solenoid structure harbouring a deep central pocket. The TPR-S binding pocket is lined with several conserved aromatic and polar residues predicted to bind a NAD -derived nucleotide in prokaryotic NAD -derived nucleotide-activated effector conflict systems. It has been acquired at the base of the choanoflagellate-animal lineage as a core component of the ASK signalosome [].
This is the N-terminal domain of the beta chain found in Drosophila melanogaster protein BDBT (a FK506-Binding Protein) which stimulates the DBT circadian function. The domain contains the DBT-binding site. The domain is structurally homologous to the peptidyl prolyl isomerase (PPIase) regions of FK506-binding proteins despite low sequence homology. BDBT is structurally related to the immunophilin FKBP51 and it shares a common domain organization consisting of PPIase-like and TPR domains with noncanonical immunophilins such as FKBP38 or FKBPL [].
Members resemble the peptide maturation dehydrogenase SagB of thiazole and oxazole modification systems, and occur in a what appears to be a new type of peptide modification system. One adjacent marker is a new type of nitrile hydratase alpha subunit-related putative precursor, , distantly related the NHLP leader peptide family . Another is a large protein, , with regions similar to adenylate cyclases and TPR proteins.
ER membrane protein complex subunit 2 (EMC2, also known as tetratricopeptide repeat protein 35) is a tetratricopeptide repeat-containing protein, and a component of the ER membrane protein complex (EMC), which is required for efficient folding of proteins in the endoplasmic reticulum (ER) []. This entry also includes TPR repeat protein Oca3 from the fission yeast Schizosaccharomyces pombe which may be involved in cell cycle regulation [].
This entry represents a domain found in trafficking protein particle complex subunit 11 (Trappc11), which is involved in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage []. The C terminus of this region contains TPR repeats.In zebrafish, Trappc11 is also known as protein foie gras. It has been shown to affect development; the mutants develop large, lipid-filled hepatocytes in the liver, resembling those in individuals with fatty liver disease [].
The Mps1 family of protein kinases is a critical regulatorof genetic stability [, ]. In yeast, Mps1 is required for the spindle checkpoint and SPBduplication []. Human Mps1, also known as TTK, is required for proper chromosome alignment on the metaphase plate and for the fidelity of chromosome segregation, and might also have a role at centrosomes[]. It is associated with cell proliferation and involved in mitotic cell cycle checkpoint control [, ]. In late mitosis, Mps1 is ubiquitinated by the APC/C and subsequently degraded []. The catalytic domain of Mps1 is in the C-terminal region, and the N-terminal region includes TPR repeats that promote homodimer formation [].
This is the N-terminal domain found in Zmiz1 proteins (Zinc finger MIZ domain-containing protein 1). Zmiz1 is a direct Notch1 cofactor that heterogeneously regulates Notch target genes. Zmiz1 directly interacts with the RAM1 domain of Notch1 through this N-terminal tetratricopeptide repeat (TPR) domain. Furthermore, it has been shown that Zmiz1 and Notch1 cooperatively recruit each other to chromatin through direct interaction via the N-terminal TPR domain resulting in a slight increase in activating histone marks and decrease of repressive histone marks. Functional analysis indicate that the N-terminal Domain of Zmiz1 is important for driving Myc transcription and proliferation indirectly [].
Tfc3 (also known as Tau138) is one of three subunits of the tauB subcomplex of yeast transcription factor IIIC. This extended winged-helix domain of tau138 appears to interact with the TPR (tetratricopeptide repeat) array of tauA subunit tau131, and may therefore play a role in linking tauA, tauB, and TFIIIB to regulate the formation of the RNA polymerase III pre-initiation complex [, ].Proteins containing this domain also include mammalian general transcription factor 3C polypeptide 1 (Gtf3c1), which is a transcription factor IIIC box B binding subunit [].
LapB (lipopolysaccharide assembly protein B) contains three major structural motifs: the N-terminal transmembrane helix, several tetratricopeptide repeats (TPR), and a C-terminal rubredoxin metal binding domain. This entry represents the rubredoxin-like metal binding domain. Rubredoxin proteins form small non-heme iron binding sites that use four cysteine residues to coordinate a single metal ion in a tetrahedral environment. Rubredoxins are most commonly found in bacterial systems, but have also been found in eukaryotes. The key features of these rubredoxin-like domains are the extended loops or 'knuckles' and the tetracysteine mode of iron binding. Structural analysis of LapB from Escherichia coli show that the rubredoxin metal binding domain is intimately bound to the TPR motifs and that this association to the TPR motifs is essential to LPS regulation and growth in vivo []. Proteins containing this domain also include RadA. In E. coli, RadA (or Sms) participates in the recombinational repair of radiation-damaged DNA in a process that uses an undamaged DNA strand in one DNA duplex to fill a DNA strand gap in a homologous sister DNA duplex. RadA carries a zinc finger at the N-terminal domain [].
Serine/threonine protein phosphatase-5 (PP5) is a member of the PPP gene family of protein phosphatases that is highly conserved among eukaryotes and widely expressed in mammalian tissues. PP5 has a C-terminal phosphatase domain and an extended N-terminal TPR (tetratricopeptide repeat) domain containing three TPR motifs [, , , , ]. This entry represents the C-terminal phosphatase domain. Proteins containing this domain also include yeast Ppt1, which is a serine/threonine phosphatase that regulates Hsp90 chaperone by affecting its ATPase and cochaperone binding activitie []. The PPP (phosphoprotein phosphatase) family is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP1, PP2A, PP2B (calcineurin), PP4, PP6, PP7, Bsu1, RdgC, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of manycellular processes [, ]. PPPs belong to the metallophosphatase (MPP) superfamily.
The GGDEF domain, which has been named after the conserved central sequence pattern GG[DE][DE]F is widespread in prokaryotes. It is typically present in multidomain proteins containing regulatory domains of signaling pathways or protein-protein or protein-ligand interaction modules, such as the response regulatory domain, the PAS/PAC domain, the HAMP domain, the GAF domain, the FHA domain or the TPR repeat. However a few single-domain proteins are also known. The GGDEF domain is involved in signal transduction and is likely to catalyze synthesis or hydrolysis of cyclic diguanylate (c-diGMP, bis(3',5')-cyclic diguanylic acid), an effector molecule that consists of two cGMP moieties bound head-to-tail [, , ].Structural studies of PleD from Caulobacter crescentus show that this domain forms a five-stranded beta sheet surrounded by helices, similar to the catalytic core of adenylate cyclase [].
The bipartite CS domain, which was named after CHORD-containing proteins and SGT1 [], is a ~100-residue protein-protein interaction module. The CS domain can be found in stand-alone form, as well as fused with other domains, such as CHORD (), SGS (), TPR (), cytochrome b5 () or b5 reductase, in multidomain proteins []. The CS domain has a compact antiparallel β-sandwich fold consisting of seven β-strands [, ]. Some proteins known to contain a CS domain are listed below []: Eukaryotic proteins of the SGT1 family. Eukaryotic Rar1, related to pathogenic resistance in plants, and to development in animals. Eukaryotic nuclear movement protein nudC. Eukaryotic proteins of the p23/wos2 family, which act as co-chaperone. Animal b5+b5R flavo-hemo cytochrome NAD(P)H oxydoreductase type B. Mammalian integrin beta-1-binding protein 2 (melusin).
BEND3 is a transcriptional repressor that associates with the nucleolar-remodeling complex (NoRC) and is involved in ribosomal DNA (rDNA) silencing []. SUMOylated BEND3 stabilizes the NoRC component Tip5 via USP21 deubiquitinase []. NorC serves as a molecular platform that recruits chromatin modifiers, such as histone deacetylases and histone methyltransferases, leading to deacetylation of histone H4 and trimethylation of H3K9 and H4K20 []. NoRC also targets histone deacetylases and histone methyltransferases to rDNA to establish a heterochromatic state that inhibits transcription activation. Hence, BEND3 and NoRC seem to play a concerted role in the maintenance of heterochromatin architecture [, ].BEND3 has also been shown to mediate Polycomb recruitment in the absence of H3K9Me3 or DNA methylation at the pericentromeric regions []. BEND3 interacts with PICH (ERCC6L), a DNA translocase required for the maintenance of chromosome stability, and stimulates its translocase and ATPase activities. This interaction occurs via an interface between a TPR domain in PICH and a BEN domain in BEND3 [].
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [].This PH-like domain is found in the regulatory region of ASK1/2/3 (also known as MAP3K5/6/15). The central regulatory region of ASK1 mediates a compact arrangement of the kinase and thioredoxin-binding domains which allows the binding of substrates for phosphorylation. This PH-like domain adopts the typical form of two antiparallel β-sheets followed by a C-terminal amphipathic helix [].
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.
Peroxisomal proteins catalyse metabolic reactions. The import of proteins from the cytosol into the peroxisomes matrix depends on more than a dozen peroxin (PEX) proteins, among which PEX5 and PEX7 serve as receptors that shuttle proteins bearing one of two peroxisome-targeting signals (PTSs) into the organelle. PEX5 is the PTS1 receptor, while PEX7 is the PTS2 receptor. In plants, PEX7 depends on PEX5 binding to deliver PTS2 cargo into the peroxisome, and PEX7 also facilitates PEX5 accumulation and import of PTS1 cargo into peroxisomes [, ]. This entry include PEX5 (also known as PTS1R) from animals, fungi and plants. This entry also includes PEX5L from vertebrates. PEX5 binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import [, , ]. Based on subcellular localization and binding properties mammalian PEX5 may function as a regulator in an early step of the PTS1 protein import process []. PEX5L acts as an accessory subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, regulating their cell-surface expression and cyclic nucleotide dependence [, ]. Interestingly, although PEX5 and PEX5L have structurally similar binding at their TPR domains, they bind to different substrates in vivo [].
Telomeres function to shield chromosome ends from degradation and end-to-end fusions, as well as preventing the activation of DNA damage checkpoints. Telomeric repeat binding factor (TRF) proteins TRF1 and TRF2 are major components of vertebrate telomeres required for regulation of telomere stability. TRF1 and TRF2 bind to telomeric DNA as homodimers. Dimerisation involves the TRF homology (TRFH) subdomain contained within the dimerisation domain. The TRFH subdomain is important not only for dimerisation, but for DNA binding, telomere localisation, and interactions with other telomeric proteins. The dimerisation domains of TRF1 and TRF2 show the same multi-helical structure, arranged in a solenoid conformation similar to TPR repeats, which can be divided into an α-α superhelix and a long alpha hairpin [].The two related human TRF proteins hTRF1 and hTRF2 form homodimers and bind directly to telomeric TTAGGG repeats via the myb DNA binding domain at the carboxy terminus []. TRF1 is implicated in telomere length regulation and TRF2 in telomere protection []. Other telomere complex associated proteins are recruited through their interaction with either TRF1 or TRF2. The fission yeast protein Taz1p (telomere-associated in Schizosaccharomyces pombe (Fission yeast) has similarity to both hTRF1 and hTRF2 and may perform the dual functions of TRF1 and TRF2 at fission yeast telomeres []. This entry represents the dimerisation domain.
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [].
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [].This domain represents a predicted non-heme-binding version of the globin domain identified in ASK1/2/3. It displays strongest affinities to the HisK-N family of sensor domains, which inhibit histidine kinase activation required for sporulation in bacteria of the firmicutes lineage. This globin domain is predicted to represent an independent sensory element recognizing a fatty acid or a related membrane-derived molecule which regulates activity of the ASK signalosome in apoptosis [].
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [].This is an uncharacterised DRHyd domain observed in MAP3K5/6/15. It potentially generates nucleotide-derived signal recognised by the TPR-S domain found in the same proteins [].
This group represents telomeric repeat-binding factors 1 (TERF1, also known as TRF1).Telomeres function to shield chromosome ends from degradation and end-to-end fusions, as well as preventing the activation of DNA damage checkpoints. Telomeric repeat binding factor (TRF) proteins TRF1 and TRF2 are major components of vertebrate telomeres required for regulation of telomere stability. TRF1 and TRF2 bind to telomeric DNA as homodimers. Dimerisation involves the TRF homology (TRFH) subdomain contained within the dimerisation domain. The TRFH subdomain is important not only for dimerisation, but for DNA binding, telomere localisation, and interactions with other telomeric proteins. The dimerisation domains of TRF1 and TRF2 show the same multi-helical structure, arranged in a solenoid conformation similar to TPR repeats, which can be divided into an α-α superhelix and a long alpha hairpin [].The two related human TRF proteins hTRF1 and hTRF2 form homodimers and bind directly to telomeric TTAGGG repeats via the myb DNA binding domain at the carboxy terminus []. TRF1 is implicated in telomere length regulation and TRF2 in telomere protection []. Other telomere complex associated proteins are recruited through their interaction with either TRF1 or TRF2. The fission yeast protein Taz1p (telomere-associated in Schizosaccharomyces pombe (Fission yeast) has similarity to both hTRF1 and hTRF2 and may perform the dual functions of TRF1 and TRF2 at fission yeast telomeres [].
This entry represents telomeric repeat-binding factor 2 (TERF2, also known as TRF2).Telomeres function to shield chromosome ends from degradation and end-to-end fusions, as well as preventing the activation of DNA damage checkpoints. Telomeric repeat binding factor (TRF) proteins TRF1 and TRF2 are major components of vertebrate telomeres required for regulation of telomere stability. TRF1 and TRF2 bind to telomeric DNA as homodimers. Dimerisation involves the TRF homology (TRFH) subdomain contained within the dimerisation domain. The TRFH subdomain is important not only for dimerisation, but for DNA binding, telomere localisation, and interactions with other telomeric proteins. The dimerisation domains of TRF1 and TRF2 show the same multi-helical structure, arranged in a solenoid conformation similar to TPR repeats, which can be divided into an α-α superhelix and a long alpha hairpin [].The two related human TRF proteins hTRF1 and hTRF2 form homodimers and bind directly to telomeric TTAGGG repeats via the myb DNA binding domain at the carboxy terminus []. TRF1 is implicated in telomere length regulation and TRF2 in telomere protection []. Other telomere complex associated proteins are recruited through their interaction with either TRF1 or TRF2. The fission yeast protein Taz1p (telomere-associated in Schizosaccharomyces pombe (Fission yeast) has similarity to both hTRF1 and hTRF2 and may perform the dual functions of TRF1 and TRF2 at fission yeast telomeres [].
The cro/C1-type HTH domain is a DNA-binding, helix-turn-helix (HTH) domain of about 50-60 residues present in transcriptional regulators. The domain is named after the transcriptional repressors cro and C1 of temperate bacteriophages 434 and lambda, respectively. Besides in bacteriophages, cro/C1-type regulators are present in prokaryotes and in eukaryotes. The helix-turn-helix DNA-binding motif is generally located in the N-terminal part of these transcriptional regulators. The C-terminal part may contain an oligomerization domain, e.g. C1 repressors and CopR act as dimers, while SinR is a tetramer. The cro/C1-type HTH domain also occurs in combination with the TPR repeat and the C-terminal part of C-5 cytosine-specific DNA methylases contains regions related to the enzymatic function.Several structures of cro/C1-type transcriptional repressors have been resolved and their DNA-binding domain encompasses five α-helices, of which the extremities are less conserved []. The helix-turn-helix motif comprises the second and third helices, the third being called the recognition helix. The HTH is involved in DNA-binding into the major groove, where the recognition helix makes most DNA-contacts. The bacteriophage repressors regulate lysogeny/lytic growth by binding with differential affinity to the operators. These operators show 2-fold symmetry and the repressors bind as dimers. Binding of the repressor to the operator positions the DNA backbone into a slightly bent twist [, ].
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [].This domain corresponds to the TRAFs-binding domain found at the N terminus of some MAP3Ks. This domain includes seven tetratricopeptide repeats (TPRs) and, together with th PH-like domain, constitutes the central regulatory domain of ASK1.
Telomeres function to shield chromosome ends from degradation and end-to-end fusions, as well as preventing the activation of DNA damage checkpoints. Telomeric repeat binding factor (TRF) proteins TRF1 and TRF2 are major components of vertebrate telomeres required for regulation of telomere stability. TRF1 and TRF2 bind to telomeric DNA as homodimers. Dimerisation involves the TRF homology (TRFH) subdomain contained within the dimerisation domain. The TRFH subdomain is important not only for dimerisation, but for DNA binding, telomere localisation, and interactions with other telomeric proteins. The dimerisation domains of TRF1 and TRF2 show the same multi-helical structure, arranged in a solenoid conformation similar to TPR repeats, which can be divided into an α-α superhelix and a long alpha hairpin [].The two related human TRF proteins hTRF1 and hTRF2 form homodimers and bind directly to telomeric TTAGGG repeats via the myb DNA binding domain at the carboxy terminus []. TRF1 is implicated in telomere length regulation and TRF2 in telomere protection []. Other telomere complex associated proteins are recruited through their interaction with either TRF1 or TRF2. The fission yeast protein Taz1p (telomere-associated in Schizosaccharomyces pombe (Fission yeast) has similarity to both hTRF1 and hTRF2 and may perform the dual functions of TRF1 and TRF2 at fission yeast telomeres []. This entry represents the dimerisation domain.
In heterotrimeric G-protein signalling, cell surface receptors (GPCRs) arecoupled to membrane-associated heterotrimers comprising a GTP-hydrolysing subunit G-alpha and a G-beta/G-gamma dimer. The inactive form contains the alpha subunit bound to GDP and complexes with the beta and gamma subunit. When the ligand is associated to thereceptor, GDP is displaced from G-alpha and GTP is bound. GTP/G-alpha complex dissociates from the trimer and associates to an effector until the intrinsic GTPase activity of G-alpha returns the protein to GDP bound form. Reassociation of GDP bound G-alpha with G-beta/G-gamma dimer terminates the signal. Several mechanisms regulate the signal output at different stage of the G-protein cascade. Two classes of intracellular proteins act as inhibitors of G protein activation: GTPase activating proteins (GAPs), which enhance GTP hydrolysis (see ),and guanine dissociation inhibitors (GDIs), which inhibit GDP dissociation.The GoLoco or G-protein regulatory (GPR) motif found in various G-proteinregulators [, ]acts as a GDI on G-alpha(i) [, ].The crystal structure of the GoLoco motif in complex with G-alpha(i) has been solved []. It consists of three small alpha helices. The highly conserved Asp-Gln-Arg triad within the GoLoco motif participates directly in GDP binding by extending the arginine side chain into the nucleotide binding pocket, highly reminiscent of the catalytic arginine finger employed in GTPase-activating protein (see ). This addition of an arginine in the binding pocket affects the interaction of GDP with G-alpha and therefore is certainly important for the GoLoco GDI activity [].Some proteins known to contain a GoLoco motif are listed below:Mammalian regulators of G-protein signalling 12 and 14 (RGS12 and RGS14), multifaceted signal transduction regulators.Loco, the drosophila RGS12 homologue.Mammalian Purkinje-cell protein-2 (Pcp2). It may function as a cell-type specific modulator for G protein-mediated cell signalling. It is uniquely expressed in cerebellar Purkinje cells and in retinal bipolar neurons.Eukaryotic Rap1GAP. A GTPase activator for the nuclear ras-related regulatory protein RAP-1A.Drosophila protein Rapsynoid (also known as Partner of Inscuteable, Pins) and its mammalian homologues AGS3 and LGN. They form a G-protein regulator family that also contains TPR repeats.
Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions []. Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk []. These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more []. Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) []. The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response [, ].This entry represents VieB-type response regulators. In Vibrio, it is part of a signal transduction pathway involved in cholera toxin production [, ].Response regulators of the microbial two-component signal transduction systems typically consist of an N-terminal CheY-like receiver (phosphoacceptor) domain and a C-terminal output (usually DNA-binding) domain. In response to an environmental stimulus, a phosphoryl group is transferred from the His residue of sensor histidine kinase to an Asp residue in the CheY-like receiver domain of the cognate response regulator [, , ]. Phosphorylation of the receiver domain induces conformational changes that activate an associated output domain, which in turn triggers the response. Phosphorylation-induced conformational changes in response regulator molecules have been demonstrated in direct structural studies [].The output domain found in this group is so far unique. In part, it contains a divergent version of TPR repeats.
