| Type |
Details |
Score |
| Publication |
| First Author: |
Nashef A |
| Year: |
2018 |
| Journal: |
J Dent Res |
| Title: |
Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility. |
| Volume: |
97 |
| Issue: |
5 |
| Pages: |
537-546 |
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•
•
•
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| Publication |
| First Author: |
Madka V |
| Year: |
2016 |
| Journal: |
Cancer Prev Res (Phila) |
| Title: |
Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo. |
| Volume: |
9 |
| Issue: |
1 |
| Pages: |
53-62 |
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•
•
•
•
|
| Publication |
| First Author: |
Staloch D |
| Year: |
2015 |
| Journal: |
J Mol Med (Berl) |
| Title: |
Gremlin is a key pro-fibrogenic factor in chronic pancreatitis. |
| Volume: |
93 |
| Issue: |
10 |
| Pages: |
1085-1093 |
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•
•
•
•
|
| Publication |
| First Author: |
Brane A |
| Year: |
2023 |
| Journal: |
Cancers (Basel) |
| Title: |
Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes. |
| Volume: |
15 |
| Issue: |
3 |
|
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•
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| Publication |
| First Author: |
Snijder EJ |
| Year: |
1995 |
| Journal: |
J Biol Chem |
| Title: |
The arterivirus Nsp2 protease. An unusual cysteine protease with primary structure similarities to both papain-like and chymotrypsin-like proteases. |
| Volume: |
270 |
| Issue: |
28 |
| Pages: |
16671-6 |
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•
•
•
•
•
|
| Protein Domain |
| Type: |
Domain |
| Description: |
Arteriviruses are enveloped, positive-stranded RNA viruses and includepathogens of major economic concern to the swine- and horse-breedingindustries:Equine arteritis virus (EAV).Porcine reproductive and respiratory syndrome virus (PRRSV).Mice actate dehydrogenase-elevating virus.Simian hemorrhagic fever virus.The arterivirus cysteine protease (AV CP) is the most carboxyl-terminallylocated member of the array of three cysteine proteinase domains present inthe amino-terminal 500 residues of the replicase polyproteins. The AV CP islocated in the amino-terminal region of nsp2 and is highly conserved amongarteriviruses. The cleavage of the nsp2|3 junction appears to be the singleprocessing step mediated by the AV CP. For EAV, it has been shown that cleavednsp2 is an essential co-factor for cleavage of the nsp4|6 site by the nsp4proteinase domain. The AV CP is an unusual Cys protease withamino acid sequence similarities to both papain-like and chymotrypsin-likeproteases. The catalytic dyad is composed of Cys and His residues [, , ]. The AV CP domain forms MEROPS peptidase family C33.The entire AV CP domain is highly conserved among arteriviruses.Among the conserved residues are a number of cysteines and one aspartateresidues [].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 precedesthe 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. |
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•
|
| Publication |
| First Author: |
Wong AC |
| Year: |
2023 |
| Journal: |
Cell |
| Title: |
Serotonin reduction in post-acute sequelae of viral infection. |
| Volume: |
186 |
| Issue: |
22 |
| Pages: |
4851-4867.e20 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Joyce MG |
| Year: |
2021 |
| Journal: |
Cell Rep |
| Title: |
SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity. |
| Volume: |
37 |
| Issue: |
12 |
| Pages: |
110143 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Fischer U |
| Year: |
2015 |
| Journal: |
Nat Genet |
| Title: |
Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. |
| Volume: |
47 |
| Issue: |
9 |
| Pages: |
1020-1029 |
|
•
•
•
•
•
|
| Protein Domain |
| Type: |
Homologous_superfamily |
| Description: |
Lysine-tRNA ligase (also knowns as lysyl-tRNA synthetase) () is an alpha 2 homodimer that belong to both class I and class II. In eubacteria and eukaryota lysine-tRNA ligases belong to class II in the same family as aspartate tRNA ligase. The class Ic lysine-tRNA ligase family is present in archaea and in a number of bacterial groups that include the alphaproteobacteria and spirochaetes[]. A refined crystal structures shows that the active site of lysU is shaped to position the substrates for the nucleophilic attack of the lysine carboxylate on the ATP alpha-phosphate. No residues are directly involved in catalysis, but a number of highly conserved amino acids and three metal ions coordinate the substrates and stabilise the pentavalent transition state. A loop close to the catalytic pocket, disordered in the lysine-bound structure, becomes ordered upon adenine binding [].The structure of LysRS-I is composed of 5 domains: a Rossmann-fold domain (domain 1), a helical insertion (Ins 1), a CP domain (domain 2), a SC-fold domain (domain 3) an α-helix bundle-like domain (domain 4) and an α-helix cage domain (domain 5).This entry represents the stem contact fold (SC-fold) domain found in Lysine tRNA ligase. |
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•
•
•
•
|
| Publication |
| First Author: |
Wassenaar AL |
| Year: |
1997 |
| Journal: |
J Virol |
| Title: |
Alternative proteolytic processing of the arterivirus replicase ORF1a polyprotein: evidence that NSP2 acts as a cofactor for the NSP4 serine protease. |
| Volume: |
71 |
| Issue: |
12 |
| Pages: |
9313-22 |
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•
•
•
•
•
|
| Publication |
| First Author: |
Gonzalez AM |
| Year: |
2011 |
| Journal: |
Fluids Barriers CNS |
| Title: |
Ecrg4 expression and its product augurin in the choroid plexus: impact on fetal brain development, cerebrospinal fluid homeostasis and neuroprogenitor cell response to CNS injury. |
| Volume: |
8 |
| Issue: |
1 |
| Pages: |
6 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Ozturk F |
| Year: |
2013 |
| Journal: |
BMC Genomics |
| Title: |
Systematic analysis of palatal transcriptome to identify cleft palate genes within TGFβ3-knockout mice alleles: RNA-Seq analysis of TGFβ3 Mice. |
| Volume: |
14 |
|
| Pages: |
113 |
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•
•
•
•
•
|
| Publication |
| First Author: |
Rayasam A |
| Year: |
2020 |
| Journal: |
J Neurosci |
| Title: |
Neonatal Stroke and TLR1/2 Ligand Recruit Myeloid Cells through the Choroid Plexus in a CX3CR1-CCR2- and Context-Specific Manner. |
| Volume: |
40 |
| Issue: |
19 |
| Pages: |
3849-3861 |
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•
•
•
•
•
|
| Publication |
| First Author: |
Cheriyan J |
| Year: |
2018 |
| Journal: |
J Neurosci |
| Title: |
Altered Excitability and Local Connectivity of mPFC-PAG Neurons in a Mouse Model of Neuropathic Pain. |
| Volume: |
38 |
| Issue: |
20 |
| Pages: |
4829-4839 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Masamune A |
| Year: |
2020 |
| Journal: |
Gastroenterology |
| Title: |
Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis. |
| Volume: |
158 |
| Issue: |
6 |
| Pages: |
1626-1641.e8 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Dolgodilina E |
| Year: |
2020 |
| Journal: |
Fluids Barriers CNS |
| Title: |
Choroid plexus LAT2 and SNAT3 as partners in CSF amino acid homeostasis maintenance. |
| Volume: |
17 |
| Issue: |
1 |
| Pages: |
17 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Zhang QW |
| Year: |
2000 |
| Journal: |
Transplantation |
| Title: |
Mixed chimerism, heart, and skin allograft tolerance in cyclophosphamide-induced tolerance. |
| Volume: |
70 |
| Issue: |
6 |
| Pages: |
906-16 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Shibata Y |
| Year: |
1985 |
| Journal: |
J Immunol |
| Title: |
The effect of hemopoietic microenvironment on splenic suppressor macrophages in congenitally anemic mice of genotype Sl/Sld. |
| Volume: |
135 |
| Issue: |
6 |
| Pages: |
3905-10 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Kanekal S |
| Year: |
1992 |
| Journal: |
Toxicol Appl Pharmacol |
| Title: |
Pharmacokinetics, metabolic activation, and lung toxicity of cyclophosphamide in C57/B16 and ICR mice. |
| Volume: |
114 |
| Issue: |
1 |
| Pages: |
1-8 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Yang ZM |
| Year: |
1996 |
| Journal: |
Biol Reprod |
| Title: |
Activation of brain-type cannabinoid receptors interferes with preimplantation mouse embryo development. |
| Volume: |
55 |
| Issue: |
4 |
| Pages: |
756-61 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Hoyle CF |
| Year: |
1998 |
| Journal: |
Hematol Oncol |
| Title: |
Engraftment of chronic myeloid leukemia in SCID mice. |
| Volume: |
16 |
| Issue: |
3 |
| Pages: |
87-100 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Dickie MM |
| Year: |
1961 |
| Journal: |
Mouse News Lett |
| Title: |
Reverse mutations in dilute and agouti |
| Volume: |
25 |
|
| Pages: |
37 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Moeller C |
| Year: |
2003 |
| Journal: |
Development |
| Title: |
Carboxypeptidase Z (CPZ) modulates Wnt signaling and regulates the development of skeletal elements in the chicken. |
| Volume: |
130 |
| Issue: |
21 |
| Pages: |
5103-11 |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
206
 |
| Fragment?: |
true |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
244
|
| Fragment?: |
true |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Novikova E |
| Year: |
2001 |
| Journal: |
Mech Dev |
| Title: |
Metallocarboxypeptidase Z is dynamically expressed in mouse development. |
| Volume: |
102 |
| Issue: |
1-2 |
| Pages: |
259-62 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Novikova EG |
| Year: |
2000 |
| Journal: |
J Biol Chem |
| Title: |
Carboxypeptidase Z is present in the regulated secretory pathway and extracellular matrix in cultured cells and in human tissues. |
| Volume: |
275 |
| Issue: |
7 |
| Pages: |
4865-70 |
|
•
•
•
•
•
|
| Protein Domain |
| Type: |
Domain |
| Description: |
This entry represents the carboxypeptidase domain (CPD) found in carboxypeptidase Z. Carboxypeptidase Z (CPZ; MEROPS identifier M14.012) belongs to subfamily M14B (N/E subfamily) of the M14 family of metallocarboxypeptidases (MCPs) []. CPZ is a secreted Zn-dependent enzyme whose biological function is largely unknown. Unlike other members of the N/E subfamily, CPZ has a bipartite structure, which consists of an N-terminal cysteine-rich domain (CRD) whose sequence is similar to Wnt-binding proteins, and a C-terminal CP catalytic domain that removes C-terminal Arg residues from substrates. CPZ is enriched in the extracellular matrix and is widely distributed during early embryogenesis [, ]. That the CRD of CPZ can bind to Wnt4 suggests that CPZ plays a role in Wnt signaling [, ].The carboxypeptidase A family can be divided into four subfamilies: M14A(carboxypeptidase A or digestive), M14B (carboxypeptidase H or regulatory), M14C (gamma-D-glutamyl-L-diamino acid peptidase I) and M14D (AGTPBP-1/Nna1-like proteins) [, ]. Members of subfamily M14B have longer C-termini than those of subfamily M14A [], and carboxypeptidase M (a member of the H family) is bound to the membrane by a glycosylphosphatidylinositol anchor, unlike the majority of the M14 family, which are soluble []. The zinc ligands have been determined as two histidines and a glutamate,and the catalytic residue has been identified as a C-terminal glutamate,but these do not form the characteristic metalloprotease HEXXH motif [, ]. Members of the carboxypeptidase A family are synthesised as inactive molecules with propeptides that must be cleaved to activate the enzyme. Structural studies of carboxypeptidases A and B reveal the propeptide to exist as a globular domain, followed by an extended α-helix; this shields the catalytic site, without specifically binding to it, while the substrate-binding site is blocked by making specific contacts [, ]. |
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•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
1122
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Harris A |
| Year: |
2000 |
| Journal: |
Mol Cell Neurosci |
| Title: |
Regenerating motor neurons express Nna1, a novel ATP/GTP-binding protein related to zinc carboxypeptidases. |
| Volume: |
16 |
| Issue: |
5 |
| Pages: |
578-96 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Wang T |
| Year: |
2006 |
| Journal: |
Mol Cell Neurosci |
| Title: |
The carboxypeptidase-like substrate-binding site in Nna1 is essential for the rescue of the Purkinje cell degeneration (pcd) phenotype. |
| Volume: |
33 |
| Issue: |
2 |
| Pages: |
200-13 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Chakrabarti L |
| Year: |
2008 |
| Journal: |
Vision Res |
| Title: |
The zinc-binding domain of Nna1 is required to prevent retinal photoreceptor loss and cerebellar ataxia in Purkinje cell degeneration (pcd) mice. |
| Volume: |
48 |
| Issue: |
19 |
| Pages: |
1999-2005 |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
1218
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
1122
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Rodriguez de la Vega M |
| Year: |
2007 |
| Journal: |
FASEB J |
| Title: |
Nna1-like proteins are active metallocarboxypeptidases of a new and diverse M14 subfamily. |
| Volume: |
21 |
| Issue: |
3 |
| Pages: |
851-65 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Gerhard DS |
| Year: |
2004 |
| Journal: |
Genome Res |
| Title: |
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |
| Volume: |
14 |
| Issue: |
10B |
| Pages: |
2121-7 |
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•
•
•
•
•
|
| Publication |
| First Author: |
Hoshino A |
| Year: |
2020 |
| Journal: |
Cell |
| Title: |
Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers. |
| Volume: |
182 |
| Issue: |
4 |
| Pages: |
1044-1061.e18 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Kolabas ZI |
| Year: |
2023 |
| Journal: |
Cell |
| Title: |
Distinct molecular profiles of skull bone marrow in health and neurological disorders. |
| Volume: |
186 |
| Issue: |
17 |
| Pages: |
3706-3725.e29 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Roychowdhury T |
| Year: |
2023 |
| Journal: |
Nat Genet |
| Title: |
Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target. |
| Volume: |
55 |
| Issue: |
11 |
| Pages: |
1831-1842 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Genzel L |
| Year: |
2020 |
| Journal: |
Curr Biol |
| Title: |
How the COVID-19 pandemic highlights the necessity of animal research. |
| Volume: |
30 |
| Issue: |
18 |
| Pages: |
R1014-R1018 |
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•
•
•
•
•
|
| Publication |
| First Author: |
Bedolla A |
| Year: |
2022 |
| Journal: |
J Neuroinflammation |
| Title: |
Diphtheria toxin induced but not CSF1R inhibitor mediated microglia ablation model leads to the loss of CSF/ventricular spaces in vivo that is independent of cytokine upregulation. |
| Volume: |
19 |
| Issue: |
1 |
| Pages: |
3 |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
277
|
| Fragment?: |
true |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
118
|
| Fragment?: |
true |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
207
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Wolf DH |
| Year: |
2004 |
| Journal: |
Biochim Biophys Acta |
| Title: |
The proteasome: a proteolytic nanomachine of cell regulation and waste disposal. |
| Volume: |
1695 |
| Issue: |
1-3 |
| Pages: |
19-31 |
|
•
•
•
•
•
|
| Publication |
| First Author: |
Reznik SE |
| Year: |
2001 |
| Journal: |
Cell Mol Life Sci |
| Title: |
Carboxypeptidases from A to z: implications in embryonic development and Wnt binding. |
| Volume: |
58 |
| Issue: |
12-13 |
| Pages: |
1790-804 |
|
•
•
•
•
•
|
| Protein Domain |
| Type: |
Domain |
| Description: |
Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation which is usually zinc, but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophillic role. Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site []. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [].This group of sequences contain a diverse range of gene families, which include metallopeptidases belonging to MEROPS peptidase family M14 (carboxypeptidase A, clan MC), subfamilies M14A and M14B.The carboxypeptidase A family can be divided into four subfamilies: M14A(carboxypeptidase A or digestive), M14B (carboxypeptidase H or regulatory), M14C (gamma-D-glutamyl-L-diamino acid peptidase I) and M14D (AGTPBP-1/Nna1-like proteins) [, ]. Members of subfamily M14B have longer C-termini than those of subfamily M14A [], and carboxypeptidase M (a member of the H family) is bound to the membrane by a glycosylphosphatidylinositol anchor, unlike the majority of the M14 family, which are soluble [].ATP/GTP binding protein (AGTPBP-1/Nna1)-like proteins are active metallopeptidases that act on cytosolic proteins such as alpha-tubulin, to remove a C-terminal tyrosine. Mutations in AGTPBP-1/Nna1 cause Purkinje cell degeneration (pcd). AGTPBP-1/Nna1-like proteins from the different phyla are highly diverse, but they all contain a unique N-terminal conserved domain right before the CP domain. It has been suggested that this N-terminal domain might act as a folding domain [, , , ].The zinc ligands have been determined as two histidines and a glutamate,and the catalytic residue has been identified as a C-terminal glutamate,but these do not form the characteristic metalloprotease HEXXH motif [, ]. Members of the carboxypeptidase A family are synthesised as inactive molecules with propeptides that must be cleaved to activate the enzyme. Structural studies of carboxypeptidases A and B reveal the propeptide to exist as a globular domain, followed by an extended α-helix; this shields the catalytic site, without specifically binding to it, while the substrate-binding site is blocked by making specific contacts [, ]. |
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•
•
•
•
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| Protein Domain |
| Type: |
Domain |
| Description: |
This entry represents the second carboxypeptidase (CP)-like domain of carboxypeptidase D (CPD; EC 3.4.17.22; MEROPS M14.016).Carboxypeptidase D (CPD) differs from all other metallocarboxypeptidases in that it contains multiple CP-like domains []. CPD belongs to the N/E-like subfamily (subfamily M14B) of the M14 family of metallocarboxypeptidases (MCPs) []. CPD is a single-chain protein containing a signal peptide, three tandem repeats of CP-like domains separated by short bridge regions, followed by a transmembrane domain, and a C-terminal cytosolic tail. The first two CP-like domains of CPD contain all of the essential active site and substrate-binding residues, while the third CP-like domain lacks critical residues necessary for enzymatic activity and is inactive towards standard CP substrates. Domain I is optimally active at pH 6.3-7.5 and prefers substrates with C-terminal Arg, whereas domain II is active at pH 5.0-6.5 and prefers substrates with C-terminal Lys [, , ]. CPD functions in the processing of proteins that transit the secretory pathway, and is present in all vertebrates as well as Drosophila[]. It is broadly distributed in all tissue types. Within cells, CPD is present in the trans-Golgi network and immature secretory vesicles, but is excluded from mature vesicles []. It is thought to play a role in the processing of proteins that are initially processed by furin or related endopeptidases present in the trans-Golgi network, such as growth factors and receptors []. CPD is implicated in the pathogenesis of lupus erythematosus (LE), it is regulated by TGF-beta in various cell types of murine and human origin and is significantly down-regulated in CD14 positive cells isolated from patients with LE. As down-regulation of CPD leads to down-modulation of TGF-beta, CPD may have a role in a positive feedback loop [].The carboxypeptidase A family can be divided into four subfamilies: M14A(carboxypeptidase A or digestive), M14B (carboxypeptidase H or regulatory), M14C (gamma-D-glutamyl-L-diamino acid peptidase I) and M14D (AGTPBP-1/Nna1-like proteins) [, ]. Members of subfamily M14B have longer C-termini than those of subfamily M14A [], and carboxypeptidase M (a member of the H family) is bound to the membrane by a glycosylphosphatidylinositol anchor, unlike the majority of the M14 family, which are soluble []. The zinc ligands have been determined as two histidines and a glutamate,and the catalytic residue has been identified as a C-terminal glutamate,but these do not form the characteristic metalloprotease HEXXH motif [, ]. Members of the carboxypeptidase A family are synthesised as inactive molecules with propeptides that must be cleaved to activate the enzyme. Structural studies of carboxypeptidases A and B reveal the propeptide to exist as a globular domain, followed by an extended α-helix; this shields the catalytic site, without specifically binding to it, while the substrate-binding site is blocked by making specific contacts [, ]. |
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| Publication |
| First Author: |
Schumann G |
| Year: |
2016 |
| Journal: |
Proc Natl Acad Sci U S A |
| Title: |
KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. |
| Volume: |
113 |
| Issue: |
50 |
| Pages: |
14372-14377 |
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| Publication |
| First Author: |
Gomis-Rüth FX |
| Year: |
1999 |
| Journal: |
EMBO J |
| Title: |
Crystal structure of avian carboxypeptidase D domain II: a prototype for the regulatory metallocarboxypeptidase subfamily. |
| Volume: |
18 |
| Issue: |
21 |
| Pages: |
5817-26 |
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| Publication |
| First Author: |
Aloy P |
| Year: |
2001 |
| Journal: |
J Biol Chem |
| Title: |
The crystal structure of the inhibitor-complexed carboxypeptidase D domain II and the modeling of regulatory carboxypeptidases. |
| Volume: |
276 |
| Issue: |
19 |
| Pages: |
16177-84 |
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| Publication |
| First Author: |
Sidyelyeva G |
| Year: |
2010 |
| Journal: |
Cell Mol Life Sci |
| Title: |
Individual carboxypeptidase D domains have both redundant and unique functions in Drosophila development and behavior. |
| Volume: |
67 |
| Issue: |
17 |
| Pages: |
2991-3004 |
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| Publication |
| First Author: |
Hoff NP |
| Year: |
2007 |
| Journal: |
J Clin Immunol |
| Title: |
Carboxypeptidase D: a novel TGF-beta target gene dysregulated in patients with lupus erythematosus. |
| Volume: |
27 |
| Issue: |
6 |
| Pages: |
568-79 |
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| Publication |
| First Author: |
Varlamov O |
| Year: |
2001 |
| Journal: |
J Cell Sci |
| Title: |
Protein phosphatase 2A binds to the cytoplasmic tail of carboxypeptidase D and regulates post-trans-Golgi network trafficking. |
| Volume: |
114 |
| Issue: |
Pt 2 |
| Pages: |
311-22 |
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| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
1377
|
| Fragment?: |
false |
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•
•
•
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| Publication |
| First Author: |
Guenet JL |
| Year: |
1978 |
| Journal: |
Mouse News Lett |
| Title: |
Mutant Stocks: Alphabetical list of named mutant genes (except T locus alleles) |
| Volume: |
59 |
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| Pages: |
50-54 |
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•
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| Publication |
| First Author: |
Allen M |
| Year: |
2012 |
| Journal: |
Neurology |
| Title: |
Novel late-onset Alzheimer disease loci variants associate with brain gene expression. |
| Volume: |
79 |
| Issue: |
3 |
| Pages: |
221-8 |
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•
|
| Publication |
| First Author: |
Pinto D |
| Year: |
2010 |
| Journal: |
Nature |
| Title: |
Functional impact of global rare copy number variation in autism spectrum disorders. |
| Volume: |
466 |
| Issue: |
7304 |
| Pages: |
368-72 |
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•
•
•
|
| Publication |
| First Author: |
Mouse Genome Sequencing Consortium. |
| Year: |
2002 |
| Journal: |
Nature |
| Title: |
Initial sequencing and comparative analysis of the mouse genome. |
| Volume: |
420 |
| Issue: |
6915 |
| Pages: |
520-62 |
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•
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| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
1006
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| Fragment?: |
false |
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•
•
•
•
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| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
862
|
| Fragment?: |
false |
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•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
886
|
| Fragment?: |
false |
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•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
540
|
| Fragment?: |
false |
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•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
418
|
| Fragment?: |
false |
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•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
346
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| Fragment?: |
false |
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•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
140
|
| Fragment?: |
false |
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•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
206
|
| Fragment?: |
true |
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•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
711
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| Fragment?: |
true |
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•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
494
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| Fragment?: |
false |
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•
•
•
|
| Publication |
| First Author: |
Rees DC |
| Year: |
1983 |
| Journal: |
J Mol Biol |
| Title: |
Refined crystal structure of carboxypeptidase A at 1.54 A resolution. |
| Volume: |
168 |
| Issue: |
2 |
| Pages: |
367-87 |
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•
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| Publication |
| First Author: |
Osterman AL |
| Year: |
1992 |
| Journal: |
J Protein Chem |
| Title: |
Primary structure of carboxypeptidase T: delineation of functionally relevant features in Zn-carboxypeptidase family. |
| Volume: |
11 |
| Issue: |
5 |
| Pages: |
561-70 |
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| Protein Domain |
| Type: |
Family |
| Description: |
Clostripain is a cysteine protease characterised from Clostridium histolyticum, and also known from Clostridium perfringens. It is a heterodimer processed from a single precursor polypeptide, using a specific Arg-|-Xaa cleavage. The older term alpha-clostripain refers to the most active, most reduced form, rather than to the product of one of several different genes. This group of cysteine peptidases belong to the MEROPS peptidase family C11 (clostripain family, clan CD).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. |
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| Protein Domain |
| Type: |
Family |
| Description: |
This group of cysteine peptidases belong to the MEROPS peptidase family C11 (clostripain family, clan CD). 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. |
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| Protein Domain |
| Type: |
Family |
| Description: |
This is a group of cysteine peptidases which constitute MEROPS peptidase family C54 (Aut2 peptidase family, clan CA).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. |
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| Protein Domain |
| Type: |
Family |
| Description: |
This group of cysteine peptidases belong to MEROPS peptidase family C8 (clan CA). The peptidases are encoded by the double stranded viral RNAs belonging to the genus Hypovirus.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. |
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•
•
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| Protein Domain |
| Type: |
Domain |
| Description: |
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.This group of cysteine peptidases belong to the MEROPS peptidase family C23 (clan CA). The type example is Carlavirus (apple stem pitting virus) endopeptidase, this thought to playa role in the post-translational cleavage of the high molecular weight primary translation products of the virus. |
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| Protein Domain |
| Type: |
Domain |
| Description: |
This group of cysteine peptidases correspond to MEROPS peptidase family C42. The type example is beet yellows virus-type papain-like endopeptidase (beet yellows virus) []. 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. |
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| Protein Domain |
| Type: |
Domain |
| Description: |
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.This group of cysteine peptidases correspond to MEROPS peptidase family C36 (clan CA). The type example is beet necrotic yellow vein furovirus-type papain-like endopeptidase (beet necrotic yellow vein virus), which is involved in processing the viral polyprotein. |
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| Protein Domain |
| Type: |
Domain |
| Description: |
This entry represents the third carboxypeptidase (CP)-like domain of Carboxypeptidase D (CPD; MEROPS identifier XM14.001; EC 3.4.17.22)(MEROPS identifier M14.950). Carboxypeptidase D (CPD) differs from all other metallocarboxypeptidases in that it contains multiple CP-like domains []. CPD belongs to the N/E-like subfamily (subfamily M14B) of the M14 family of metallocarboxypeptidases (MCPs) []. CPD is a single-chain protein containing a signal peptide, three tandem repeats of CP-like domains separated by short bridge regions, followed by a transmembrane domain, and a C-terminal cytosolic tail. The first two CP-like domains of CPD contain all of the essential active site and substrate-binding residues, while the third CP-like domain lacks critical residues necessary for enzymatic activity and is inactive towards standard CP substrates. Domain I is optimally active at pH 6.3-7.5 and prefers substrates with C-terminal Arg, whereas domain II is active at pH 5.0-6.5 and prefers substrates with C-terminal Lys [, , ]. CPD functions in the processing of proteins that transit the secretory pathway, and is present in all vertebrates as well as Drosophila[]. It is broadly distributed in all tissue types. Within cells, CPD is present in the trans-Golgi network and immature secretory vesicles, but is excluded from mature vesicles []. It is thought to play a role in the processing of proteins that are initially processed by furin or related endopeptidases present in the trans-Golgi network, such as growth factors and receptors []. CPD is implicated in the pathogenesis of lupus erythematosus (LE), it is regulated by TGF-beta in various cell types of murine and human origin and is significantly down-regulated in CD14 positive cells isolated from patients with LE. As down-regulation of CPD leads to down-modulation of TGF-beta, CPD may have a role in a positive feedback loop [].The carboxypeptidase A family can be divided into four subfamilies: M14A(carboxypeptidase A or digestive), M14B (carboxypeptidase H or regulatory), M14C (gamma-D-glutamyl-L-diamino acid peptidase I) and M14D (AGTPBP-1/Nna1-like proteins) [, ]. Members of subfamily M14B have longer C-termini than those of subfamily M14A [], and carboxypeptidase M (a member of the H family) is bound to the membrane by a glycosylphosphatidylinositol anchor, unlike the majority of the M14 family, which are soluble []. The zinc ligands have been determined as two histidines and a glutamate,and the catalytic residue has been identified as a C-terminal glutamate,but these do not form the characteristic metalloprotease HEXXH motif [, ]. Members of the carboxypeptidase A family are synthesised as inactive molecules with propeptides that must be cleaved to activate the enzyme. Structural studies of carboxypeptidases A and B reveal the propeptide to exist as a globular domain, followed by an extended α-helix; this shields the catalytic site, without specifically binding to it, while the substrate-binding site is blocked by making specific contacts [, ]. |
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| Publication |
| First Author: |
Novikova EG |
| Year: |
1999 |
| Journal: |
J Biol Chem |
| Title: |
Characterization of the enzymatic properties of the first and second domains of metallocarboxypeptidase D. |
| Volume: |
274 |
| Issue: |
41 |
| Pages: |
28887-92 |
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| Publication |
| First Author: |
Tan F |
| Year: |
1997 |
| Journal: |
Biochem J |
| Title: |
Sequence of human carboxypeptidase D reveals it to be a member of the regulatory carboxypeptidase family with three tandem active site domains. |
| Volume: |
327 ( Pt 1) |
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| Pages: |
81-7 |
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| Publication |
| First Author: |
Varlamov O |
| Year: |
1999 |
| Journal: |
J Biol Chem |
| Title: |
Localization of metallocarboxypeptidase D in AtT-20 cells. Potential role in prohormone processing. |
| Volume: |
274 |
| Issue: |
21 |
| Pages: |
14759-67 |
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| Publication |
| First Author: |
Kalinina E |
| Year: |
2007 |
| Journal: |
FASEB J |
| Title: |
A novel subfamily of mouse cytosolic carboxypeptidases. |
| Volume: |
21 |
| Issue: |
3 |
| Pages: |
836-50 |
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| Publication |
| First Author: |
Chen JM |
| Year: |
1998 |
| Journal: |
FEBS Lett |
| Title: |
Identification of the active site of legumain links it to caspases, clostripain and gingipains in a new clan of cysteine endopeptidases. |
| Volume: |
441 |
| Issue: |
3 |
| Pages: |
361-5 |
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| Publication |
| First Author: |
Zong Y |
| Year: |
2004 |
| Journal: |
Structure |
| Title: |
The structure of sortase B, a cysteine transpeptidase that tethers surface protein to the Staphylococcus aureus cell wall. |
| Volume: |
12 |
| Issue: |
1 |
| Pages: |
105-12 |
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| Publication |
| First Author: |
Barrett AJ |
| Year: |
1982 |
| Journal: |
Biochem J |
| Title: |
L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L. |
| Volume: |
201 |
| Issue: |
1 |
| Pages: |
189-98 |
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| Publication |
| First Author: |
Ziebuhr J |
| Year: |
2000 |
| Journal: |
J Gen Virol |
| Title: |
Virus-encoded proteinases and proteolytic processing in the Nidovirales. |
| Volume: |
81 |
| Issue: |
Pt 4 |
| Pages: |
853-79 |
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| Publication |
| First Author: |
Peng CW |
| Year: |
2001 |
| Journal: |
J Virol |
| Title: |
Functional specialization and evolution of leader proteinases in the family Closteroviridae. |
| Volume: |
75 |
| Issue: |
24 |
| Pages: |
12153-60 |
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| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
393
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| Fragment?: |
false |
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| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
458
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| Fragment?: |
false |
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•
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| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
474
|
| Fragment?: |
false |
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•
•
•
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| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
271
|
| Fragment?: |
false |
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•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
455
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
654
|
| Fragment?: |
false |
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•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
234
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
396
|
| Fragment?: |
false |
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•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
121
|
| Fragment?: |
true |
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•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
143
|
| Fragment?: |
false |
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•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
213
|
| Fragment?: |
false |
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