Cobra CRISP Functions as an Inflammatory Modulator via a Novel Zn2+- and Heparan Sulfate-dependent Transcriptional Regulation of Endothelial Cell Adhesion Molecules*
| Autor: | Je Hung Kuo, Chun-Jung Chen, Jai Shin Liu, Yin Cheng Hsieh, Jeng Jiann Chiu, Wen-guey Wu, Shao Chen Lee, Yu Ling Wang, Yu Tsung Shih |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Transcription
Genetic Molecular Conformation Glycobiology and Extracellular Matrices Gene Expression Plasma protein binding Biology Biochemistry Cell Line chemistry.chemical_compound Protein structure X-Ray Diffraction Cell Adhesion Animals Humans Elapidae Binding site Cell adhesion Molecular Biology Cells Cultured Elapid Venoms Binding Sites Kinase Cell adhesion molecule Endothelial Cells NF-κB Cell Biology Heparan sulfate Cell biology Protein Structure Tertiary Zinc chemistry Heparitin Sulfate Inflammation Mediators Cell Adhesion Molecules Protein Binding |
| Popis: | 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 Zn(2+) 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 Zn(2+)-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. |
| Databáze: | OpenAIRE |
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