Crystal Structure of Human Carboxypeptidase M, a Membrane-Bound Enzyme that Regulates Peptide Hormone Activity

摘要: Carboxypeptidase M (CPM), an extracellular glycosylphosphatidyl-inositol(GPI)-anchored membrane glycoprotein belonging to the CPN/E subfamily of "regulatory" metallo-carboxypeptidases, specifically removes C-terminal basic residues from peptides and proteins. Due its wide distribution in human tissues, CPM is believed play important roles control peptide hormone growth factor activity at cell surface, membrane-localized degradation We have crystallized GPI-free CPM, determined refined 3.0A crystal structure. The structure analysis reveals that consists a 295 residue N-terminal catalytic domain similar duck CPD-2 (but only distantly related CPA/B), adjacent 86 beta-sandwich characteristic family but more conically shaped than equivalent CPD-2, unique, partially disordered 25 extension which GPI membrane-anchor post-translationally attached. Through this anchor, presumably via some positively charged side-chains domain, molecule may interact with such way active centre will face alongside, i.e. well suited other membrane-bound protein substrates or small peptides. Modelling part natural substrate Arg(6)-Met-enkephalin into site shows S1' pocket particularly designed accommodate P1'-Arg residues, agreement preference for cleaving Arg.