<br>MMP-3 与三螺旋胶原蛋白相互作用的结构研究介绍了该酶在组织重塑中的新作用。,Scientific Reports

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MMP-3 与三螺旋胶原蛋白相互作用的结构研究介绍了该酶在组织重塑中的新作用。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-12-11 , DOI: 10.1038/s41598-019-55266-9
Szymon W Manka _{1,

2} , Dominique Bihan ₃ , Richard W Farndale ₃

Affiliation

基质金属蛋白酶-3 (MMP-3) 参与胚胎发育、器官形态发生和伤口愈合过程中的正常细胞外基质周转，以及与动脉瘤、癌症、关节炎和心力衰竭相关的组织破坏。尽管MMP-3无法裂解三螺旋胶原蛋白，但它仍然可以与其结合，但结合的机制、位置和作用尚不清楚。我们使用胶原蛋白工具包（包含胶原蛋白 II 和 III 的整个螺旋结构域的三螺旋肽库）来绘制 MMP-3 相互作用位点图谱。该酶可识别 II 型胶原蛋白上的 5 个位点和 III 型胶原蛋白上的 3 个位点。它们共享一个甘氨酸-苯丙氨酸-羟脯氨酸/丙氨酸 (GFO/A) 基序，该基序被酶以上下文相关的方式识别。 MMP-3 酶原 (proMMP-3) 或 MMP-3 的单独催化 (Cat) 和血红素结合蛋白 (Hpx) 结构域均不与肽相互作用，这表明两个结构域与三螺旋的协同结合。 Toolkit 结合数据与分子模型相结合，使我们能够推断出 MMP-3 的假定胶原蛋白结合模式，其中所有三个胶原蛋白链都与跨 Cat 和 HPx 域的谷中的酶接触。观察到的结合模式揭示了 MMP-3 如何调节胶原蛋白周转并与调节细胞粘附和增殖的各种胶原蛋白结合蛋白竞争。

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Structural studies of the MMP-3 interaction with triple-helical collagen introduce new roles for the enzyme in tissue remodelling.

Matrix metalloproteinase-3 (MMP-3) participates in normal extracellular matrix turnover during embryonic development, organ morphogenesis and wound healing, and in tissue-destruction associated with aneurysm, cancer, arthritis and heart failure. Despite its inability to cleave triple-helical collagens, MMP-3 can still bind to them, but the mechanism, location and role of binding are not known. We used the Collagen Toolkits, libraries of triple-helical peptides that embrace the entire helical domains of collagens II and III, to map MMP-3 interaction sites. The enzyme recognises five sites on collagen II and three sites on collagen III. They share a glycine-phenylalanine-hydroxyproline/alanine (GFO/A) motif that is recognised by the enzyme in a context-dependent manner. Neither MMP-3 zymogen (proMMP-3) nor the individual catalytic (Cat) and hemopexin (Hpx) domains of MMP-3 interact with the peptides, revealing cooperative binding of both domains to the triple helix. The Toolkit binding data combined with molecular modelling enabled us to deduce the putative collagen-binding mode of MMP-3, where all three collagen chains make contacts with the enzyme in the valley running across both Cat and Hpx domains. The observed binding pattern casts light on how MMP-3 could regulate collagen turnover and compete with various collagen-binding proteins regulating cell adhesion and proliferation.

更新日期：2019-12-11

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