Glycan Activation of a Sheddase: Electrostatic Recognition between Heparin and proMMP-7

• Published in: Structure (London) Vol. 25; no. 7; pp. 1100 - 1110.e5
• Main Authors: Fulcher, Yan G., Prior, Stephen H., Masuko, Sayaka, Li, Lingyun, Pu, Dennis, Zhang, Fuming, Linhardt, Robert J., Van Doren, Steven R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 05-07-2017
• Subjects: allosteric effector site; Catalytic Domain; Enzyme Precursors - chemistry; Enzyme Precursors - metabolism; glycan-protein interaction; glycosaminoglycan; heparan sulfate-binding protein; Heparin - chemistry; Heparin - metabolism; heparin-binding protein; Humans; matrilysin; Metalloendopeptidases - chemistry; Metalloendopeptidases - metabolism; Molecular Docking Simulation; paramagnetic relaxation enhancement; protease; Protein Binding; Proteolysis; spin label; Static Electricity; zymogen; allosteric effector site; protease; paramagnetic relaxation enhancement; heparin-binding protein; spin label; zymogen; glycan-protein interaction; glycosaminoglycan; heparan sulfate-binding protein; matrilysin
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2017.05.019

Heparan sulfate proteoglycans activate the matrix metalloproteinase-7 zymogen (proMMP-7) and recruit it in order to shed proteins from cell surfaces. This occurs in uterine and mammary epithelia, bacterial killing, lung healing, and tumor cell signaling. Basic tracks on proMMP-7 recognize polyanionic heparin, according to nuclear magnetic resonance and mutations disruptive of maturation. Contacts and proximity measurements guided docking of a heparin octasaccharide to proMMP-7. The reducing end fits into a basic pocket in the pro-domain while the chain continues toward the catalytic domain. Another oligosaccharide traverses a basic swath remote on the catalytic domain and inserts its reducing end into a slot formed with the basic C terminus. This latter association appears to support allosteric acceleration of proteolysis. The modes of binding account for extended, heterogeneous assemblies of proMMP-7 with heparinoids during maturation and for bridging to pro-α-defensins and proteoglycans. These associations support proteolytic release of activities at epithelial cell surfaces.
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•Heparin oligosaccharides bind two basic tracks and pockets of proMMP-7•Both modes of binding support proteolytic maturation of the zymogen•Heparin chains perturb the termini of proMMP-7•Allostery and shedding may be attributed to GAG binding remote on catalytic domain
Glycosaminoglycans recruit the protease MMP-7 to growth factors, receptors, and antibacterial proteins for maturation and shedding from cell surfaces. Fulcher et al. orient heparin chains on basic strips on the zymogen using NMR in solution and mutations that interfere in heparin-triggered maturation.