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

Alex Bayés, Theodoros Tsetsenis, Salvador Ventura, Josep Vendrell, Francesc X. Aviles, Georgia Sotiropoulou

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61 Citations (Scopus)

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 (pro-hK6) 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 (D81-K244). Site-directed mutagenesis was used to investigate the basis for the intrinsic catalytic activity and the activation mechanism of pro-hK6. A single substitution R80→Q stabilized the activity of the mature enzyme, while substitution of the active site serine (S197→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 S460-V461 resulted in the generation of angiostatin, an endogenous inhibitor of angiogenesis and metastatic growth. Copyright © by Walter de Gruyter.
Original languageEnglish
Pages (from-to)517-524
JournalBiological Chemistry
Volume385
DOIs
Publication statusPublished - 1 Jun 2004

Keywords

  • Angiostatin
  • Autoactivation
  • Human kallikrein 6
  • Serine protease
  • Site-directed mutagenesis

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