Cobra CRISP functions as an inflammatory modulator via a novel Zn 2+- and heparan sulfate-dependent transcriptional regulation of endothelial cell adhesion molecules

Yu Ling Wang, Je Hung Kuo, Shao Chen Lee, Jai Shin Liu, Yin Cheng Hsieh, Yu Tsung Shih, Chun Jung Chen, Jeng Jiann Chiu, Wen Guey Wu

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Cysteine-rich secretory proteins (CRISPs) have been identified as a toxin family in most animal venoms with biological functions mainly associated with the ion channel activity of cysteine-rich domain (CRD). CRISPs also bind to Zn2+ at their N-terminal pathogenesis-related (PR-1) domain, but their function remains unknown. Interestingly, similar the Zn 2+-binding site exists in all CRISP family, including those identified in a wide range of organisms. Here, we report that the CRISP from Naja atra (natrin) could induce expression of vascular endothelial cell adhesion molecules, i.e. intercellular adhesion molecule-1, vascular adhesion molecule-1, and E-selectin, to promote monocytic cell adhesion in a heparan sulfate (HS)- and Zn2+-dependent manner. Using specific inhibitors and small interfering RNAs, the activation mechanisms are shown to involve both mitogen-activated protein kinases and nuclear factor-κB. Biophysical characterization of natrin by using fluorescence, circular dichroism, and x-ray crystallographic methods further reveals the presence of two Zn 2+-binding sites for natrin. The strong binding site is located near the putative Ser-His-Glu catalytic triad of the N-terminal domain. The weak binding site remains to be characterized, but it may modulate HS binding by enhancing its interaction with long chain HS. Our results strongly suggest that natrin may serve as an inflammatory modulator that could perturb the wound-healing process of the bitten victim by regulating adhesion molecule expression in endothelial cells. Our finding uncovers a new aspect of the biological role of CRISP family in immune response and is expected to facilitate future development of new therapeutic strategy for the envenomed victims.

Original languageEnglish
Pages (from-to)37872-37883
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number48
DOIs
Publication statusPublished - Nov 26 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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