Abstract：
Human α2-macroglobulin (hα2M) is a multidomain protein with a plethora of essential functions, including transport of signaling molecules and endopeptidase inhibition in innate immunity. Here, we dissected the molecular mechanism of the inhibitory function of the ∼720-kDa hα2M tetramer through eight cryo–electron microscopy (cryo-EM) structures of complexes from human plasma. In the native complex, the hα2M subunits are organized in two flexible modules in expanded conformation, which enclose a highly porous cavity in which the proteolytic activity of circulating plasma proteins is tested. Cleavage of bait regions exposed inside the cavity triggers rearrangement to a compact conformation, which closes openings and entraps the prey proteinase. After the expanded-to-compact transition, which occurs independently in the four subunits, the reactive thioester bond triggers covalent linking of the proteinase, and the receptor-binding domain is exposed on the tetramer surface for receptor-mediated clearance from circulation. These results depict the molecular mechanism of a unique suicidal inhibitory trap.
摘要：
人α2-巨球蛋白（hα2M）是一种具有大量基本功能的多域蛋白，包括先天免疫中信号分子的转运和内肽酶抑制。这里,我们通过人类血浆复合物的八个低温电子显微镜（cryo-EM）结构，解剖了〜720-kDahα2M四聚体抑制功能的分子机制。在原生情结中，Hα2M亚基以扩展的构象组织在两个柔性模块中，它包围一个高度多孔的空腔，在其中测试循环血浆蛋白的蛋白水解活性。暴露在空腔内的诱饵区域的分裂触发重排为紧凑的构象，关闭开口并捕获猎物蛋白酶。在从扩展到紧凑的过渡之后，在四个亚基中独立发生，反应性硫酯键触发蛋白酶的共价连接，并且受体结合结构域暴露在四聚体表面上用于受体介导的从循环中清除。这些结果描述了独特的自杀抑制陷阱的分子机制。
