Structure of protease-cleaved Escherichia coli α-2-macroglobulin reveals a putative mechanism of conformational activation for protease entrapment.
Structure of protease-cleaved Escherichia coli α-2-macroglobulin reveals a putative mechanism of conformational activation for protease entrapment.
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DOI：
10.1107/s1399004715008548
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Walker D
中科院分区：
文献类型：
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作者：
Fyfe CD;Grinter R;Josts I;Mosbahi K;Roszak AW;Cogdell RJ;Wall DM;Burchmore RJ;Byron O;Walker D
蛋白酶裂解的E.描述了大肠杆菌α-2-巨球蛋白，揭示了蛋白酶抑制所必需的激活和构象变化的假定机制。细菌α-2-巨球蛋白被认为在防御中作为破坏外膜的宿主蛋白酶的广谱抑制剂起作用。本文描述了蛋白酶裂解的大肠杆菌α-2-巨球蛋白的X射线结构，揭示了蛋白酶抑制所必需的激活和构象变化的假定机制。在这种竞争机制中，诱饵区结构域的蛋白酶切割导致该结构域的固有无序区域的解链，这破坏了维持E.大肠杆菌α-2-巨球蛋白的灭活形式。由此产生的整体构象变化导致蛋白酶的捕获和与攻击蛋白酶共价连接的硫酯键的激活。由于大肠杆菌α-2-巨球蛋白和人α-2-巨球蛋白在结构和结构域上的相似性，这种蛋白酶激活机制可能在该组的不同成员中起作用。
The X-ray structure of protease-cleaved E. coli α-2-macroglobulin is described, which reveals a putative mechanism of activation and conformational change essential for protease inhibition. Bacterial α-2-macroglobulins have been suggested to function in defence as broad-spectrum inhibitors of host proteases that breach the outer membrane. Here, the X-ray structure of protease-cleaved Escherichia coli α-2-macroglobulin is described, which reveals a putative mechanism of activation and conformational change essential for protease inhibition. In this competitive mechanism, protease cleavage of the bait-region domain results in the untethering of an intrinsically disordered region of this domain which disrupts native interdomain interactions that maintain E. coli α-2-macroglobulin in the inactivated form. The resulting global conformational change results in entrapment of the protease and activation of the thioester bond that covalently links to the attacking protease. Owing to the similarity in structure and domain architecture of Escherichia coli α-2-macroglobulin and human α-2-macroglobulin, this protease-activation mechanism is likely to operate across the diverse members of this group.