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.
LanguageEnglish
Pages862-867
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume366
Issue number3
DOIs
Publication statusPublished - 15 Feb 2008

Fingerprint

Enzyme Precursors
Heparin
Chemical activation
Cathepsin L
procathepsin L
Extracellular Matrix
Tumors
Gels
Mutation
Substrates
Processing

Keywords

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

Cite this

Fairhead, Michael ; Kelly, S.M. ; van der Walle, Christopher F. / A heparin binding motif on the pro-domain of human procathepsin L mediates zymogen destabilization and activation. In: Biochemical and Biophysical Research Communications. 2008 ; Vol. 366, No. 3. pp. 862-867.
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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.",
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A heparin binding motif on the pro-domain of human procathepsin L mediates zymogen destabilization and activation. / Fairhead, Michael; Kelly, S.M.; van der Walle, Christopher F.

In: Biochemical and Biophysical Research Communications, Vol. 366, No. 3, 15.02.2008, p. 862-867.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A heparin binding motif on the pro-domain of human procathepsin L mediates zymogen destabilization and activation

AU - Fairhead, Michael

AU - Kelly, S.M.

AU - van der Walle, Christopher F.

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AB - 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.

KW - cathepsin L

KW - heparin

KW - pro-domain

KW - binding motif

KW - cysteine protease

KW - circular dichroism

KW - fluorescence

KW - pharmacology

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