Accessible Requires Authentication Published by De Gruyter June 1, 2005

Human kallikrein 6 activity is regulated via an autoproteolytic mechanism of activation/inactivation

A. Bayés, T. Tsetsenis, S. Ventura, J. Vendrell, F.X. Aviles and G. Sotiropoulou
From the journal

Abstract

Human kallikrein 6 (protease M/zyme/neurosin) is a serine protease that has been suggested to be a serum biomarker for ovarian cancer and may also be involved in pathologies of the CNS. The precursor form of human kallikrein 6 (proh-K6) was overexpressed in Pichia pastoris and found to be autoprocessed to an active but unstable mature enzyme that subsequently yielded the inactive, self-cleavage product, hK6 (D[81]K[244]). Site-directed mutagenesis was used to investigate the basis for the intrinsic catalytic activity and the activation mechanism of pro-hK6. A single substitution R[80]->Q stabilized the activity of the mature enzyme, while substitution of the active site serine (S[197]->A) resulted in complete loss of hK6 proteolytic activity and facilitated protein production. Our data suggest that the enzymatic activity of hK6 is regulated by an autoactivation/autoinactivation mechanism. Mature hK6 displayed a trypsin-like activity against synthetic substrates and human plasminogen was identified as a putative physiological substrate for hK6, as specific cleavage at the plasminogen internal bond S[460]-V[461] resulted in the generation of angiostatin, an endogenous inhibitor of angiogenesis and metastatic growth.

:
Published Online: 2005-06-01
Published in Print: 2004-06-07

Copyright © 2004 by Walter de Gruyter GmbH & Co. KG