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Seven secretory mammalian kexin-like subtilases have been identified that cleave a variety of precursor proteins at monobasic and dibasic residues. The recently characterized pyrolysin-like subtilase SKI-1 cleaves proproteins at nonbasic residues. In this work we describe the properties of a proteinase K-like subtilase, neural apoptosis-regulated convertase 1 (NARC-1), representing the ninth member of the secretory subtilase family. Biosynthetic and microsequencing analyses of WT and mutant enzyme revealed that human and mouse pro-NARC-1 are autocatalytically and intramolecularly processed into NARC-1 at the (Y,I)VV(V,L)(L,M)↓ motif, a site that is representative of its enzymic specificity. In vitro peptide processing studies and/or Ala substitutions of the P1–P5 sites suggested that hydrophobic/aliphatic residues are more critical at P1, P3, and P5 than at P2 or P4. NARC-1 expression is highest in …