Structure of a PE-PPE-EspG complex from Mycobacterium tuberculosis reveals molecular specificity of ESX protein secretion
Structure of a PE-PPE-EspG complex from Mycobacterium tuberculosis reveals molecular specificity of ESX protein secretion
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DOI：
10.1073/pnas.1409345111
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发表时间：
2014-10-14
影响因子：
11.1
通讯作者：
Cox, Jeffery S.
中科院分区：
文献类型：
--
作者：
Ekiert, Damian C.;Cox, Jeffery S.
结核分枝杆菌基因组近10%的编码容量致力于两个高度扩张和神秘的蛋白质家族，称为PE和PPE，其中一些是重要的毒力/免疫原性因子，在感染期间通过一种独特的替代分泌系统分泌，称为VII型。PE-PPE蛋白在感染过程中如何发挥作用，以及它们如何通过结核分枝杆菌的五个不同的III型分泌系统[ESAT-6分泌系统(ESX)]转运到细菌表面，目前还知之甚少。在这里，我们报道了一种与ESX分泌相关蛋白G(ESPG)结合的PE-PPE异源二聚体的晶体结构，它采用了一种新的折叠。这种PE-PPE-ESPG复合体，以及另外两个ESPG的结构，表明ESPG作为一个适配器，通过与PPE结构域的广泛相互作用识别特定的PE-PPE蛋白质复合体，并将它们运送到ESX机器进行分泌。令人惊讶的是，结核分枝杆菌大多数PE-PPE蛋白的分泌可能是由ESX-5系统的ESPG介导的，这突显了ESX-5在分枝杆菌发病机制中的重要性。此外，我们的结果表明，PE-PPE结构域作为ESPGs读出的顺式作用靶向序列，揭示了通过不同的ESX途径分泌的分子特异性。
Nearly 10% of the coding capacity of the Mycobacterium tuberculosis genome is devoted to two highly expanded and enigmatic protein families called PE and PPE, some of which are important virulence/immunogenicity factors and are secreted during infection via a unique alternative secretory system termed "type VII." How PE-PPE proteins function during infection and how they are translocated to the bacterial surface through the five distinct type VII secretion systems [ESAT-6 secretion system (ESX)] of M. tuberculosis is poorly understood. Here, we report the crystal structure of a PE-PPE heterodimer bound to ESX secretion-associated protein G (EspG), which adopts a novel fold. This PE-PPE-EspG complex, along with structures of two additional EspGs, suggests that EspG acts as an adaptor that recognizes specific PE-PPE protein complexes via extensive interactions with PPE domains, and delivers them to ESX machinery for secretion. Surprisingly, secretion of most PE-PPE proteins in M. tuberculosis is likely mediated by EspG from the ESX-5 system, underscoring the importance of ESX-5 in mycobacterial pathogenesis. Moreover, our results indicate that PE-PPE domains function as cis-acting targeting sequences that are read out by EspGs, revealing the molecular specificity for secretion through distinct ESX pathways.