Substrate-engaged type III secretion system structures reveal gating mechanism for unfolded protein translocation.
Substrate-engaged type III secretion system structures reveal gating mechanism for unfolded protein translocation.
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DOI：
10.1038/s41467-021-21143-1
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发表时间：
2021-03-09
影响因子：
16.6
通讯作者：
Marlovits TC
中科院分区：
文献类型：
--
作者：
Miletic S;Fahrenkamp D;Goessweiner-Mohr N;Wald J;Pantel M;Vesper O;Kotov V;Marlovits TC
许多细菌病原体依靠有毒力的 III 型分泌系统 (T3SS) 或注射体来移位效应蛋白以建立感染。注射体的核心成分是针复合体，它组装穿过细菌包膜和宿主细胞膜的连续导管以介导效应蛋白易位。然而，III 型分泌的分子原理仍然难以捉摸。在这里，我们报告了活性沙门氏菌鼠伤寒血清型针状复合物在两种功能状态下与效应蛋白SptP结合的结构，揭示了完整的800Å长的分泌管道，并揭示了输出装置（EA）子复合物在III型分泌中的关键作用。未折叠的底物通过 SpaQ 蛋白形成的亲水性收缩进入 EA，从而实现侧链独立的底物运输。上图，由 SpaP 蛋白形成的蛋氨酸垫圈充当门，可膨胀以容纳底物，同时防止渗漏孔的形成。穿过栅极后，可移动的 SpaR 环首先折叠起来，然后支持基板传输。总之，这些发现为通过 T3SS 进行底物易位奠定了分子基础，并提高了我们对细菌致病性和运动性的理解。有毒力的 III 型分泌系统 (T3SS) 或注射体使病原菌能够将效应蛋白直接注射到宿主细胞的细胞质中。与效应蛋白结合的针复合物的结构揭示了完整的分泌通道，并提供了对通过 T3SS 的底物易位机制的见解。
Many bacterial pathogens rely on virulent type III secretion systems (T3SSs) or injectisomes to translocate effector proteins in order to establish infection. The central component of the injectisome is the needle complex which assembles a continuous conduit crossing the bacterial envelope and the host cell membrane to mediate effector protein translocation. However, the molecular principles underlying type III secretion remain elusive. Here, we report a structure of an active Salmonella enterica serovar Typhimurium needle complex engaged with the effector protein SptP in two functional states, revealing the complete 800Å-long secretion conduit and unraveling the critical role of the export apparatus (EA) subcomplex in type III secretion. Unfolded substrates enter the EA through a hydrophilic constriction formed by SpaQ proteins, which enables side chain-independent substrate transport. Above, a methionine gasket formed by SpaP proteins functions as a gate that dilates to accommodate substrates while preventing leaky pore formation. Following gate penetration, a moveable SpaR loop first folds up to then support substrate transport. Together, these findings establish the molecular basis for substrate translocation through T3SSs and improve our understanding of bacterial pathogenicity and motility. Virulent type III secretion systems (T3SSs) or injectisomes enable pathogenic bacteria to inject effector proteins directly into the host cell cytoplasm. Structures of a needle complex engaged with the effector protein reveal the complete secretion channel and provide insights into the mechanism of substrate translocation through T3SSs.
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作者：
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