Heparinoids Activate a Protease, Secreted by Mucosa and Tumors, via Tethering Supplemented by Allostery

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• 作者：Yan G. Fulcher ; Raghavendar Reddy Sanganna Gari ; Nathan C. Frey ; Fuming Zhang ; Robert J. Linhardt ; Gavin M. King ; Steven R. Van Doren
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：April 18, 2014
• 年：2014
• 卷：9
• 期：4
• 页码：957-966
• 全文大小：556K
• 年卷期：v.9,no.4(April 18, 2014)
• ISSN：1554-8937

文摘

Activation by glycosaminoglycans (GAGs) is an emerging trend among extracellular proteases important in disease. ProMMP-7, the zymogen of a matrix metalloproteinase secreted by mucosal epithelial and tumor cells, is activated at their surfaces by sulfated GAGs, but how? ProMMP-7 is activated in trans by representative heparin oligosaccharides in a length-dependent manner, with a large jump in activation at lengths of 16 monosaccharides. Imaging by atomic force microscopy visualized small complexes of proMMP-7 molecules linked by 8-mer lengths of heparinoids and extended assembles formed with 16-mer lengths of heparin. Complexes of proMMP-7 with polydisperse heparin or heparan sulfate were more diverse. Heparinoids evidently accelerate activation by tethering multiple proMMP-7 molecules together for proteolytic attack among neighbors. Removal of either the prodomain or C-terminal peptide sequence of KRSNSRKK from MMP-7 prevents formation of the long arrays induced by heparin 16-mers or heparan sulfate. The role of the C-terminus in activation assays suggests it contributes to remote, allosteric binding of GAGs. Enhancement of proteolytic velocity of MMP-by GAGs indicates them to be effectors of V-type allostery. GAGs from proteoglycans appear to assemble proMMP-7 molecules for activation, an event preceding its tumorigenic or antibacterial proteolytic activities at cell surfaces.