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238  structures 4696  species 0  interactions 26263  sequences 444  architectures

Family: Peptidase_M14 (PF00246)

Summary: Zinc carboxypeptidase

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This is the Wikipedia entry entitled "Zinc carboxypeptidase". More...

Zinc carboxypeptidase Edit Wikipedia article

Zinc carboxypeptidase
Identifiers
SymbolPeptidase_M14
PfamPF00246
InterProIPR000834
PROSITEPDOC00123
SCOP21cbx / SCOPe / SUPFAM

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

  1. ^ a b c d Rawlings ND, Barrett AJ (1995). "Evolutionary families of metallopeptidases". Meth. Enzymol. 248: 183–228. PMID 7674922.
  2. ^ 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)
  3. ^ 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)
  4. ^ 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)
This article incorporates text from the public domain Pfam and InterPro: IPR000834

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External database links

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.

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 SpoIIP

Alignments

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...

View options

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)
RP15
(4502)
RP35
(10871)
RP55
(23020)
RP75
(34125)
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PP/heatmap 1            

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(66)
Full
(26263)
Representative proteomes UniProt
(72670)
RP15
(4502)
RP35
(10871)
RP55
(23020)
RP75
(34125)
Alignment:
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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)
RP15
(4502)
RP35
(10871)
RP55
(23020)
RP75
(34125)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download  

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 View help on the curation process

Seed source: Prosite & Pfam-B_4832 (Release 7.5)
Previous IDs: Zn_carbOpept;
Type: Domain
Sequence Ontology: SO:0000417
Author: Finn RD , Bateman A
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 View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.6 21.6
Trusted cut-off 21.6 21.6
Noise cut-off 21.5 21.5
Model length: 287
Family (HMM) version: 27
Download: download the raw HMM for this family

Species distribution

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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.

Protein Predicted structure External Information
A0A044QT89 View 3D Structure Click here
A0A044RDN4 View 3D Structure Click here
A0A044RHB3 View 3D Structure Click here
A0A044RJD0 View 3D Structure Click here
A0A044RYE1 View 3D Structure Click here
A0A044S3Q8 View 3D Structure Click here
A0A044S3R8 View 3D Structure Click here
A0A044S558 View 3D Structure Click here
A0A044S583 View 3D Structure Click here
A0A044T666 View 3D Structure Click here
A0A044VIC8 View 3D Structure Click here
A0A077YWE9 View 3D Structure Click here
A0A077YXD5 View 3D Structure Click here
A0A077Z5G2 View 3D Structure Click here
A0A077Z6P8 View 3D Structure Click here
A0A077Z9J8 View 3D Structure Click here
A0A077ZB29 View 3D Structure Click here
A0A077ZC21 View 3D Structure Click here
A0A077ZDI0 View 3D Structure Click here
A0A077ZI17 View 3D Structure Click here
A0A077ZK17 View 3D Structure Click here
A0A0D2GVR6 View 3D Structure Click here
A0A0H2UKN9 View 3D Structure Click here
A0A0H3GW98 View 3D Structure Click here
A0A0H5S1A8 View 3D Structure Click here
A0A0J9XNA4 View 3D Structure Click here
A0A0K0DRY1 View 3D Structure Click here
A0A0K0DT02 View 3D Structure Click here
A0A0K0DTS5 View 3D Structure Click here
A0A0K0DVA7 View 3D Structure Click here
A0A0K0DXB9 View 3D Structure Click here
A0A0K0DZ51 View 3D Structure Click here
A0A0K0DZK8 View 3D Structure Click here
A0A0K0DZZ9 View 3D Structure Click here
A0A0K0E0D1 View 3D Structure Click here
A0A0K0E4W0 View 3D Structure Click here
A0A0K0E4Y4 View 3D Structure Click here
A0A0K0E546 View 3D Structure Click here
A0A0K0E5G2 View 3D Structure Click here
A0A0K0E5G8 View 3D Structure Click here