Summary: Zinc carboxypeptidase
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Zinc carboxypeptidase Edit Wikipedia article
| Zinc carboxypeptidase | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||||
| Symbol | Peptidase_M14 | ||||||||||
| Pfam | PF00246 | ||||||||||
| InterPro | IPR000834 | ||||||||||
| PROSITE | PDOC00123 | ||||||||||
| SCOP2 | 1cbx / SCOPe / SUPFAM | ||||||||||
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The carboxypeptidase A family can be divided into two subfamilies: carboxypeptidase H (regulatory) and carboxypeptidase A (digestive)[1]. Members of the H family have longer C-termini than those of family A[2], 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[1].
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[1][3]. 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 alpha-helix; this shields the catalytic site, without specifically binding to it, while the substrate-binding site is blocked by making specific contacts[1][4].
Other examples of protein families in this entry include:
- Intron maturase
- Putative mitochondrial processing peptidase alpha subunit
- Superoxide dismutase [Mn] (EC 1.15.1.1)
- Asparagine synthetase [glutamine-hydrolysing] 3 (EC 6.3.5.4)
- Glucose-6-phosphate isomerase (EC 5.3.1.9)
Human proteins containing this domain
AEBP1; AGBL1; AGBL2; AGBL3; AGBL4; AGBL5; AGTPBP1; CPA1; CPA2; CPA3; CPA4; CPA5; CPA6; CPB1; CPB2; CPD; CPE; CPM; CPN1; CPO; CPXM1; CPXM2; CPZ;
References
- ^ a b c d Rawlings ND, Barrett AJ (1995). "Evolutionary families of metallopeptidases". Meth. Enzymol. 248: 183–228. PMID 7674922.
- ^ Osterman AL, Grishin NV, Smulevitch SV, Zagnitko OP, Matz MV, Stepanov VM, Revina LP (1992). "Primary structure of carboxypeptidase T: delineation of functionally relevant features in Zn-carboxypeptidase family". J. Protein Chem. 11 (5): 561–570. PMID 1449602.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Lipscomb WN, Rees DC, Lewis M (1983). "Refined crystal structure of carboxypeptidase A at 1.54 A resolution". J. Mol. Biol. 168 (2): 367–387. PMID 6887246.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Huber R, Guasch A, Coll M, Aviles FX (1992). "Three-dimensional structure of porcine pancreatic procarboxypeptidase A. A comparison of the A and B zymogens and their determinants for inhibition and activation". J. Mol. Biol. 224 (1): 141–157. PMID 1548696.
{{cite journal}}: CS1 maint: multiple names: authors list (link)
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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
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No Pfam abstract.
Internal database links
| SCOOP: | AstE_AspA CarboxypepD_reg DUF2817 |
| Similarity to PfamA using HHSearch: | AstE_AspA DUF2817 |
External database links
| HOMSTRAD: | cpa |
| MEROPS: | M14 |
| PRINTS: | PR00765 |
| PROSITE: | PDOC00123 |
| SCOP: | 1cbx |
This tab holds annotation information from the InterPro database.
InterPro entry IPR000834
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 [ PUBMED:7674922 ]. 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 [ PUBMED:7674922 ].
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) [ PUBMED:7674922 , PUBMED:17244818 ]. Members of subfamily M14B have longer C-termini than those of subfamily M14A [ PUBMED:1449602 ], 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 [ PUBMED:7674922 ].
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 [ PUBMED:17244817 , PUBMED:11083920 , PUBMED:16952463 , PUBMED:18602413 ].
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 [ PUBMED:7674922 , PUBMED:6887246 ]. 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 alpha-helix; this shields the catalytic site, without specifically binding to it, while the substrate-binding site is blocked by making specific contacts [ PUBMED:7674922 , PUBMED:1548696 ].
Gene Ontology
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
| Molecular function | zinc ion binding (GO:0008270) |
| metallocarboxypeptidase activity (GO:0004181) | |
| Biological process | proteolysis (GO:0006508) |
Domain organisation
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Pfam Clan
This family is a member of clan Peptidase_MH (CL0035), which has the following description:
This clan contains peptidases belonging to MEROPS clan MH, MC and MF. We also include Nicastrin that is part of the gamma secretase complex and not known to be a peptidase.
The clan contains the following 17 members:
Amidase_3 AstE_AspA DUF2817 DUF4910 FGase Gamma_PGA_hydro Glycolytic Ncstrn_small Nicastrin Peptidase_M14 Peptidase_M17 Peptidase_M18 Peptidase_M20 Peptidase_M28 Peptidase_M42 Peptidase_M99 SpoIIPAlignments
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
| Seed (66) |
Full (26263) |
Representative proteomes | UniProt (72670) |
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| RP15 (4502) |
RP35 (10871) |
RP55 (23020) |
RP75 (34125) |
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| HTML | |||||||
| PP/heatmap | 1 | ||||||
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key:
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
| Seed (66) |
Full (26263) |
Representative proteomes | UniProt (72670) |
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|---|---|---|---|---|---|---|---|
| RP15 (4502) |
RP35 (10871) |
RP55 (23020) |
RP75 (34125) |
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| Raw Stockholm | |||||||
| Gzipped | |||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logo
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
Trees
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
Curation
| Seed source: | Prosite & Pfam-B_4832 (Release 7.5) |
| Previous IDs: | Zn_carbOpept; |
| Type: | Domain |
| Sequence Ontology: | SO:0000417 |
| Author: |
Finn RD  , Bateman A
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| Number in seed: | 66 |
| Number in full: | 26263 |
| Average length of the domain: | 248.6 aa |
| Average identity of full alignment: | 17 % |
| Average coverage of the sequence by the domain: | 44.84 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 287 | ||||||||||||
| Family (HMM) version: | 27 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Colour assignments
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Structures
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Peptidase_M14 domain has been found. There are 238 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.
