Ubp1 (also known as LBP-1) is involved in transcriptional regulation from early development to terminal differentiation. It regulates alpha-globin in erythroid cells and P450scc (the cholesterol side-chain cleavage enzyme, cytochrome) in human placenta []. Human Ubp1 is known to be induced by HIV type I infection in lymphocytes; it represses HIV transcription by preventing the binding of TFIID to the virus promoter []. Ubp1 might also be part of a network controlling blood pressure []. Ubp1 contains an N-terminal DNA-binding CP2 domain and a central SAM domain. Ubp1 protein isoforms are able to form dimers via their SAM domain [].
Ubiquitin carboxyl-terminal hydrolases (UCH) () []are thiol proteases that recognise and hydrolyse the peptide bond at the C-terminal glycine of ubiquitin. These enzymes are involved in the processing of poly-ubiquitin precursors as well as that of ubiquinated proteins. The deubiquitinsing proteases can be split into 2 size ranges, 20-30kDa() and 100-200kDa []: the second class consist of large proteins (800 to 2000 residues) that belong to the peptidase family C19, and this group is currently represented by yeast UBP1 []. This entry includes the peptidase domain of ubiquitin-specific peptidase 38 (USP38; MEROPS identifier C19.056), which belongs to the second group of deubiquitinsing proteases. It has specificity for 'Lys-63'-linked ubiquitin chains [].
Deubiquitinating enzymes (DUB) form a large family of cysteine protease that can deconjugate ubiquitin or ubiquitin-like proteins (see ) from ubiquitin-conjugated proteins. All DUBs contain a catalytic domain surrounded by one or more subdomains, some of which contribute to target recognition. The ~120-residue DUSP (domain present in ubiquitin-specific proteases) domain is one of these specific subdomains. Single or tandem DUSP domains are located both N- and C-terminal to the ubiquitin carboxyl-terminal hydrolase catalytic core domain (see ) []. The DUSP domain displays a tripod-like AB3 fold with a three-helix bundle and a three-stranded anti-parallel β-sheet resembling the legs and seat of the tripod. Conserved residues are predominantly involved in hydrophobic packing interactions within the three α-helices. The most conserved DUSP residues, forming the PGPI motif, are flanked by two long loops that vary both in length and sequence. The PGPI motif packs against the three-helix bundle and is highly ordered []. The function of the DUSP domain is unknown but it may play a role in protein/protein interaction or substrate recognition. This domain is associated with ubiquitin carboxyl-terminal hydrolase family 2 (, MEROPS peptidase family C19). They are a family 100 to 200kDa peptides which includes the Ubp1 ubiquitin peptidase from yeast; others include: Mammalian ubiquitin carboxyl-terminal hydrolase 4 (USP4),Mammalian ubiquitin carboxyl-terminal hydrolase 11 (USP11), Mammalian ubiquitin carboxyl-terminal hydrolase 15 (USP15), Mammalian ubiquitin carboxyl-terminal hydrolase 20 (USP20), Mammalian ubiquitin carboxyl-terminal hydrolase 32 (USP32), Vertebrate ubiquitin carboxyl-terminal hydrolase 33 (USP33), Vertebrate ubiquitin carboxyl-terminal hydrolase 48 (USP48).
This entry contains the ubiquitin-like domain of ubiquitin-specific peptidase 48 (USP48; MEROPS identifier C19.068). In animals, USP48 is found in the nucleus where it trims long Lys48-linked free and substrate-anchored ubiquitin-chains, rather than completely disassembling them; a catalytic property only shared with ataxin-3 and otubain-1. USP48 ubiquitin-chain-trimming activity is regulated by casein-kinase-2-mediated phosphorylation in response to cytokine-stimulation. USP48 controls the turnover of activated NF-kB/RelA in the nucleus together with the CSN and contributes to a timely control of immune responses [].In plants the homologue of USP48 is known as USP26, which should not be confused with USP26 from mammals. USP26 deubiquitinates histone H2B and is required for heterochromatin silencing [, ].Ubiquitin carboxyl-terminal hydrolases (UCH) () []are thiol proteases that recognise and hydrolyse the peptide bond at the C-terminal glycine of ubiquitin. These enzymes are involved in the processing of poly-ubiquitin precursors as well as that of ubiquinated proteins. The deubiquitinsing proteases can be split into 2 size ranges, 20-30kDa() and 100-200kDa []: the second class consist of large proteins (800 to 2000 residues) that belong to the peptidase family C19, and this group is currently represented by yeast UBP1 [].
Ubiquitin carboxyl-terminal hydrolases (UCH) () []are thiol proteases that recognise and hydrolyse the peptide bond at the C-terminal glycine of ubiquitin. These enzymes are involved in the processing of poly-ubiquitin precursors as well as that of ubiquinated proteins. The deubiquitinsing proteases can be split into 2 size ranges, 20-30kDa() and 100-200kDa []: the second class consist of large proteins (800 to 2000 residues) that belong to the peptidase family C19, and this group is currently represented by yeast UBP1 []. This entry contains the peptidase domain for ubiquitin-specific peptidase 48 (USP48; MEROPS identifier C19.068). In animals, USP48 is found in the nucleus where it trims long Lys48-linked free and substrate-anchored ubiquitin-chains, rather than completely disassembling them; a catalytic property only shared with ataxin-3 and otubain-1. USP48 ubiquitin-chain-trimming activity is regulated by casein-kinase-2-mediated phosphorylation in response to cytokine-stimulation. USP48 controls the turnover of activated NF-kB/RelA in the nucleus together with the CSN and contributes to a timely control of immune responses [].In plants, the gene name is USP26, which should not be confused with USP26 from mammals. USP26 deubiquitinates histone H2B and is required for heterochromatin silencing [].
Deubiquitinating enzymes (DUB) form a large family of cysteine protease that can deconjugate ubiquitin or ubiquitin-like proteins (see ) from ubiquitin-conjugated proteins. All DUBs contain a catalytic domain surrounded by one or more subdomains, some of which contribute to target recognition. The ~120-residue DUSP (domain present in ubiquitin-specific proteases) domain is one of these specific subdomains. Single or tandem DUSP domains are located both N- and C-terminal to the ubiquitin carboxyl-terminal hydrolase catalytic core domain (see ) []. The DUSP domain displays a tripod-like AB3 fold with a three-helix bundle and a three-stranded anti-parallel β-sheet resembling the legs and seat of the tripod. Conserved residues are predominantly involved in hydrophobic packing interactions within the three α-helices. The most conserved DUSP residues, forming the PGPI motif, are flanked by two long loops that vary both in length and sequence. The PGPI motif packs against the three-helix bundle and is highly ordered []. The function of the DUSP domain is unknown but it may play a role in protein/protein interaction or substrate recognition. This domain is associated with ubiquitin carboxyl-terminal hydrolase family 2 (, MEROPS peptidase family C19). They are a family 100 to 200kDa peptides which includes the Ubp1 ubiquitin peptidase from yeast; others include: Mammalian ubiquitin carboxyl-terminal hydrolase 4 (USP4),Mammalian ubiquitin carboxyl-terminal hydrolase 11 (USP11), Mammalian ubiquitin carboxyl-terminal hydrolase 15 (USP15), Mammalian ubiquitin carboxyl-terminal hydrolase 20 (USP20), Mammalian ubiquitin carboxyl-terminal hydrolase 32 (USP32), Vertebrate ubiquitin carboxyl-terminal hydrolase 33 (USP33), Vertebrate ubiquitin carboxyl-terminal hydrolase 48 (USP48).
Ubiquitin carboxyl-terminal hydrolases (UCH) () []are thiol proteases that recognise and hydrolyse the peptide bond at the C-terminal glycine of ubiquitin. These enzymes are involved in the processing of poly-ubiquitin precursors as well as that of ubiquinated proteins. The deubiquitinsing proteases can be split into 2 size ranges, 20-30kDa() and 100-200kDa []: the second class consist of large proteins (800 to 2000 residues) that belong to the peptidase family C19, and this group is currently represented by yeast UBP1 []. UCH thiol proteases contain an N-terminal catalytic domain sometimes followed by C-terminal extensions that mediate protein-protein interactions []. This entry represents the catalytic domain of UCH proteins of the UBP1 group.A cysteine peptidase is a proteolytic enzyme that hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile. Hydrolysis involves usually a catalytic triad consisting of the thiol group of the cysteine, the imidazolium ring of a histidine, and a third residue, usually asparagine or aspartic acid, to orientate and activate the imidazolium ring. In only one family of cysteine peptidases, is the role of the general base assigned to a residue other than a histidine: in peptidases from family C89 (acid ceramidase) an arginine is the general base. Cysteine peptidases can be grouped into fourteen different clans, with members of each clan possessing a tertiary fold unique to the clan. Four clans of cysteine peptidases share structural similarities with serine and threonine peptidases and asparagine lyases. From sequence similarities, cysteine peptidases can be clustered into over 80 different families []. Clans CF, CM, CN, CO, CP and PD contain only one family.Cysteine peptidases are often active at acidic pH and are therefore confined to acidic environments, such as the animal lysosome or plant vacuole. Cysteine peptidases can be endopeptidases, aminopeptidases, carboxypeptidases, dipeptidyl-peptidases or omega-peptidases. They are inhibited by thiol chelators such as iodoacetate, iodoacetic acid, N-ethylmaleimide or p-chloromercuribenzoate.Clan CA includes proteins with a papain-like fold. There is a catalytic triad which occurs in the order: Cys/His/Asn (or Asp). A fourth residue, usually Gln, is important for stabilising the acyl intermediate that forms during catalysis, and this precedes the active site Cys. The fold consists of two subdomains with the active site between them. One subdomain consists of a bundle of helices, with the catalytic Cys at the end of one of them, and the other subdomain is a β-barrel with the active site His and Asn (or Asp). There are over thirty families in the clan, and tertiary structures have been solved for members of most of these. Peptidases in clan CA are usually sensitive to the small molecule inhibitor E64, which is ineffective against peptidases from other clans of cysteine peptidases [].Clan CD includes proteins with a caspase-like fold. Proteins in the clan have an α/β/α sandwich structure. There is a catalytic dyad which occurs in the order His/Cys. The active site His occurs in a His-Gly motif and the active site Cys occurs in an Ala-Cys motif; both motifs are preceded by a block of hydrophobic residues []. Specificity is predominantly directed towards residues that occupy the S1 binding pocket, so that caspases cleave aspartyl bonds, legumains cleave asparaginyl bonds, and gingipains cleave lysyl or arginyl bonds.Clan CE includes proteins with an adenain-like fold. The fold consists of two subdomains with the active site between them. One domain is a bundle of helices, and the other a β-barrell. The subdomains are in the opposite order to those found in peptidases from clan CA, and this is reflected in the order of active site residues: His/Asn/Gln/Cys. This has prompted speculation that proteins in clans CA and CE are related, and that members of one clan are derived from a circular permutation of the structure of the other.Clan CL includes proteins with a sortase B-like fold. Peptidases in the clan hydrolyse and transfer bacterial cell wall peptides. The fold shows a closed β-barrel decorated with helices with the active site at one end of the barrel []. The active site consists of a His/Cys catalytic dyad.Cysteine peptidases with a chymotrypsin-like fold are included in clan PA, which also includes serine peptidases. Cysteine peptidases that are N-terminal nucleophile hydrolases are included in clan PB. Cysteine peptidases with a tertiary structure similar to that of the serine-type aspartyl dipeptidase are included in clan PC. Cysteine peptidases with an intein-like fold are included in clan PD, which also includes asparagine lyases.
