Homodimerization via a leucine zipper motif is required for enzymatic activity of quiescent cell proline dipeptidase

Quiescent cell proline dipeptidase (QPP) is an intracellular serine proteas e that is also secreted upon cellular activation. This enzyme cleaves N-ter minal Xaa-Pro dipeptides from proteins, an unusual substrate specificity sh ared with dipeptidyl peptidase IV (CD26/DPPIV), QPP is a 58-kDa protein tha t elutes as a 120-130-kDa species from gel filtration, indicating that it f orms a homodimer, We analyzed this dimerization with in vivo co-immunopreci pitation assays. The amino acid sequence of QPP revealed a putative leucine zipper motif, and mutational analyses indicated that this leucine zipper i s required for homodimerization. The leucine zipper mutants showed a comple te lack of enzymatic activity, suggesting that homodimerization is importan t for QPP function. On the other hand, an enzyme active site mutant retaine d its ability to homodimerize. These data are the first to demonstrate a ro le for a leucine zipper motif in a proteolytic enzyme and suggest that leuc ine zipper motifs play a role in mediating dimerization of a diverse array of proteins.