A heparin binding motif on the pro-domain of human procathepsin L mediates zymogen destabilization and activation

Michael Fairhead, S.M. Kelly, Christopher F. van der Walle

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The molecular mechanism by which heparin modulates the processing of procathepsin L in the extracellular environment is proposed. We show that heparin reduces the stability of the pro form of cathepsin L at pH 5 by binding to a putative heparin binding motif (BBXB) in the pro-domain. Mutations to this motif on procathepsin L reduce heparin binding affinity and heparin-induced destabilization; in contrast, heparin only slightly destabilizes the mature cathepsin L domain. Gel analysis further shows that heparin makes procathepsin L a much better substrate for cathepsin L. Thus, heparin enhances the rate of zymogen activation by destabilization upon binding to the BBXB motif. Determining the mechanism by which procathepsin L is activated in the extracellular matrix is important to the understanding of the role that cathepsin L plays in tumour invasion.
Original languageEnglish
Pages (from-to)862-867
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume366
Issue number3
DOIs
Publication statusPublished - 15 Feb 2008

Keywords

  • cathepsin L
  • heparin
  • pro-domain
  • binding motif
  • cysteine protease
  • circular dichroism
  • fluorescence
  • pharmacology

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