Human leukocyte-derived arginine aminopeptidase. The third member of the oxytocinase subfamily of aminopeptidases

In this study we report the cloning and characterization of a novel human Aminopeptidase, which we designate leukocyte-derived arginine Aminopeptidase (L-RAP). The sequence encodes a 960-amino acid protein with significant homology to placental leucine Aminopeptidase and adipocyte-derived leucine Aminopeptidase. The predicted L-RAP contains the HEXXH(X)18E zinc-binding motif, which is characteristic of the M1 family of zinc metallopeptidases. Phylogenetic analysis indicates that L-RAP forms a distinct subfamily with placental leucine Aminopeptidase and adipocyte-derived leucine Aminopeptidase in the M1 family. Immunocytochemical analysis indicates that L-RAP is located in the lumenal side of the endoplasmic reticulum. Among various synthetic substrates tested, L-RAP revealed a preference for arginine, establishing that the Enzyme is a novel arginine Aminopeptidase with restricted substrate specificity. In addition to natural Hormones such as angiotensin III and kallidin, L-RAP cleaved various N-terminal extended precursors to major histocompatibility complex class I-presented antigenic Peptides. Like other proteins involved in antigen presentation, L-RAP is induced by interferon-gamma. These results indicate that L-RAP is a novel Aminopeptidase that can trim the N-terminal extended precursors to antigenic Peptides in the endoplasmic reticulum.