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

Significance Statement

The metalloprotease MMP-7 has received attention as sheddase and activator of anti-bacterial defenses on mucosal epithelial cells and in progression of mucosal tumors. Activation of the pro-form of MMP-7 via heavily sulfated glycosaminoglycans (GAGs)  is an important control point for the emergence of its proteolytic activities at these cell surfaces. This new work makes clear that this activation is associated with the GAGs clustering proMMP-7 molecules together so that they can proteolytically activate one another in trans. The allosteric acceleration of proteolysis evident in this paper could also enhance the maturation of the pro-form to the activated form of the enzyme.  The key GAG-dependent assembly depends on both the prodomain and C-terminus, suggesting points of vulnerability for intervening in the activation process. However, it should be kept in mind that hypothetical therapeutic agents that prevent activation of proMMP-7 may introduce side effects of preventing healthy MMP-7-dependent activation of bactericidal innate immunity in the gut and lung.

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Journal Reference

Fulcher YG, Sanganna Gari RR, Frey NC, Zhang F, Linhardt RJ, King GM, Van Doren SR.

ACS Chem Biol. 2014 Feb 10.

Department of Biochemistry and Department of Physics and Astronomy, University of Missouri , Columbia, Missouri 65211, United States.

 

Abstract

 

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.

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