A heparin binding motif on the pro-domain of human procathepsin L mediates zymogen destabilization and activation.
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.
Fairhead
Michael
M
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK.
Kelly
Sharon M
SM
van der Walle
Christopher F
CF
D001665:Binding Sites; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010843:Pichia / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary
D004792:Enzyme Precursors; D006493:Heparin; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L