Carboxypeptidase A, carboxypeptidase domain (IPR034248)

Short name: CPA_M14_CPD

Overlapping homologous superfamilies


Domain relationships


This entry represents the carboxypeptidase domain (CPD) found in carboxypeptidase (CP) A (CPA; MEROPS identifier M14.001). CPA belongs to subfamily M14B (A/B subfamily) of the M14 family of metallocarboxypeptidases (MCPs) [PMID: 7674922]. CPA enzymes generally favour hydrophobic residues. A/B subfamily enzymes are normally synthesized as inactive precursors containing preceding signal peptide, followed by a globular N-terminal pro-region linked to the enzyme; these proenzymes are called procarboxypeptidases. The procarboxypeptidase A (PCPA) is produced by the exocrine pancreas and stored as a stable zymogen in the pancreatic granules until secretion into the digestive tract occurs. Proteins containing this domain includes carboxypeptidases A1, A2 (M14.002) and A4 (M14.017). There are slightly different specificities, with A1 preferring aliphatic and small aromatic residues, and A2 and A4 preferring the bulkier aromatic side chains [PMID: 8806703, PMID: 19245716]. CPA4, detected in hormone-regulated tissues, is thought to play a role in prostate cancer [PMID: 19245716].

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]. 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].

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.