Characterization of carboxypeptidase A6, an extracellular matrix peptidase.
Carboxypeptidase A6 (CPA6) is a member of the M14 metallocarboxypeptidase family that is highly expressed in the adult mouse olfactory bulb and broadly expressed in embryonic brain and other tissues. A disruption in the human CPA6 gene is linked to Duane syndrome, a defect in the abducens nerve/lateral rectus muscle connection. In this study the cellular distribution, processing, and substrate specificity of human CPA6 were investigated. The 50-kDa pro-CPA6 is routed through the constitutive secretory pathway, processed by furin or a furin-like enzyme into the 37-kDa active form, and secreted into the extracellular matrix. CPA6 cleaves the C-terminal residue from a range of substrates, including small synthetic substrates, larger peptides, and proteins. CPA6 has a preference for large hydrophobic C-terminal amino acids as well as histidine. Peptides with a penultimate glycine or proline are very poorly cleaved. Several neuropeptides were found to be processed by CPA6, including Met- and Leu-enkephalin, angiotensin I, and neurotensin. Whereas CPA6 converts enkephalin and neurotensin into forms known to be inactive toward their receptors, CPA6 converts inactive angiotensin I into the biologically active angiotensin II. Taken together, these data suggest a role for CPA6 in the regulation of neuropeptides in the extracellular environment within the olfactory bulb and other parts of the brain.
Lyons
Peter J
PJ
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Callaway
Myrasol B
MB
Fricker
Lloyd D
LD
D000803:Angiotensin I / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000378:metabolism; D043422:Carboxypeptidases A / Q000737:chemistry* / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology*; D045683:Furin / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D009496:Neurotensin / Q000378:metabolism; D009830:Olfactory Bulb / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary
D010455:Peptides; D009496:Neurotensin; D006639:Histidine; D000803:Angiotensin I; D043422:Carboxypeptidases A; D045683:Furin