Pathways & interactions
Peptidase M14, carboxypeptidase A (IPR000834)
Short name: Peptidase_M14
- Peptidase M14, carboxypeptidase A (IPR000834)
- AEBP1/CPX, carboxypeptidase domain (IPR034243)
- At5g42320-like, carboxypeptidase domain (IPR034269)
- Carboxypeptidase A, carboxypeptidase domain (IPR034248)
- Carboxypeptidase A6 (IPR033843)
- Carboxypeptidase B, carboxypeptidase domain (IPR034253)
- Carboxypeptidase B2 (IPR033849)
- Carboxypeptidase D, carboxypeptidase-like domain 1 (IPR034241)
- Carboxypeptidase D, carboxypeptidase-like domain 2 (IPR034224)
- Carboxypeptidase D, carboxypeptidase-like domain 3 (IPR033848)
- Carboxypeptidase E, carboxypeptidase domain (IPR034232)
- Carboxypeptidase M N-terminal domain (IPR033842)
- Carboxypeptidase O (IPR033850)
- Carboxypeptidase T (IPR033810)
- Cytosolic aminopeptidase 1 (IPR033852)
- ENP1, carboxypeptidase domain (IPR034274)
- Insect gut carboxypeptidase-like, carboxypeptidase domain (IPR034223)
- Metallocarboxypeptidase Z, carboxypeptidase domain (IPR034239)
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 [PMID: 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 [PMID: 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) [PMID: 7674922, PMID: 17244818]. Members of subfamily M14B have longer C-termini than those of subfamily M14A [PMID: 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 [PMID: 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 [PMID: 17244817, PMID: 11083920, PMID: 16952463, PMID: 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 [PMID: 7674922, PMID: 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 [PMID: 7674922, PMID: 1548696].