Proteolytic activation of prochemerin by kallikrein 7 breaks an ionic linkage and results in C-terminal rearrangement

Biochem J. 2013 Jun 1;452(2):271-80. doi: 10.1042/BJ20121880.

Abstract

The excessive accumulation of adipose tissue in obesity is associated with multiple inflammatory dermatological diseases. Chemerin, a chemoattractant adipokine, dependent on proteolytical activation, is highly expressed in skin. Different proteases have been reported to activate prochemerin, but none is inherently expressed in human skin. In the present study, we identified a tissue-specific protease and investigated the underlying mechanism of activation at the molecular level. We characterized human KLK7 (kallikrein 7) as a prochemerin processing protease in vitro converting prochemerin into active chemerinF(156). The activating truncation by the protease might trigger a structural rearrangement leading to an increased affinity of chemerin to CMKLR1 (chemokine-like receptor 1). Molecular modelling and experimental data suggest an underlying ionic interaction in prochemerin C-terminal domains. These findings provide a general molecular basis for the necessity of C-terminal processing of prochemerin. Moreover, immunohistochemistry was used to investigate prochemerin, KLK7 and the recently identified KLK7 inhibitor vaspin expression in human skin biopsies, and distinct co-localization in psoriatic biopsies was observed. On the basis of these results, it is hypothesized that KLK7 activity may contribute to the development of psoriatic lesions as a consequence of excessive chemerin activation and impaired protease activity regulation by vaspin. Therefore this interaction represents an interesting target for psoriasis therapy and treatment of other obesity-related diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Chemokines / chemistry*
  • Chemokines / genetics
  • Chemokines / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Kallikreins / genetics
  • Kallikreins / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Protein Precursors / chemistry*
  • Protein Precursors / genetics
  • Protein Precursors / metabolism*
  • Proteolysis*
  • Psoriasis / enzymology
  • Psoriasis / metabolism
  • Receptors, Chemokine / metabolism

Substances

  • CMKLR1 protein, human
  • Chemokines
  • Intercellular Signaling Peptides and Proteins
  • Peptide Fragments
  • Protein Precursors
  • RARRES2 protein, human
  • Receptors, Chemokine
  • KLK7 protein, human
  • Kallikreins