小柯机器人

德国结构系统生物学中心Thomas C. Marlovits研究团队揭示VII型分枝杆菌分泌系统的结构和动力学。这一研究成果于2021年5月12日在线发表在国际学术期刊《自然》上。

研究人员表示，结核分枝杆菌是人类最重要的传染病之一，每年导致140万人死亡。专门的蛋白质转运系统，称为VII型分泌系统（T7SS），对于这种病原体的毒力至关重要，并且对于营养和代谢物在分枝杆菌细胞包膜中的转运至关重要。

研究人员报道了完整的结核分枝杆菌T7SS内膜复合物结构。研究人员展示了2.3 MDa的ESX-5组装体（其中包含165个跨膜螺旋）如何通过MycP₅蛋白酶重组并稳定。MycP₅的三聚体顶部是由三个EccB₅二聚体形成的圆顶状小室，而MycP₅的蛋白水解位点面向空腔。这个空间提示了中央的分泌和处理管道。没有MycP₅的复合物显示EccB₅装配的破坏和灵活性的增加，这突出了MycP₅对于复杂完整性的重要性。

在EccB₅-MycP₅腔室下方，EccC₅ ATP酶的二聚体组装成三束，每束具有四个跨膜螺旋，它们共同密封了潜在的中央分泌通道。单个细胞质EccC₅结构域采用两个独特的构象，可能反映了不同的分泌状态。这项工作提出了蛋白质运输的一种新机制，并提供了一种结构支架来帮助开发针对这种主要人类病原体的药物。

附：英文原文

Title: Structure and dynamics of a mycobacterial type VII secretion system

Author: Catalin M. Bunduc, Dirk Fahrenkamp, Jiri Wald, Roy Ummels, Wilbert Bitter, Edith N. G. Houben, Thomas C. Marlovits

Issue&Volume: 2021-05-12

Abstract: Mycobacterium tuberculosis is the cause of one of the most important infectious diseases in humans, which leads to 1.4 million deaths every year1. Specialized protein transport systems—known as type VII secretion systems (T7SSs)—are central to the virulence of this pathogen, and are also crucial for nutrient and metabolite transport across the mycobacterial cell envelope2,3. Here we present the structure of an intact T7SS inner-membrane complex of M. tuberculosis. We show how the 2.32-MDa ESX-5 assembly, which contains 165 transmembrane helices, is restructured and stabilized as a trimer of dimers by the MycP5 protease. A trimer of MycP5 caps a central periplasmic dome-like chamber that is formed by three EccB5 dimers, with the proteolytic sites of MycP5 facing towards the cavity. This chamber suggests a central secretion and processing conduit. Complexes without MycP5 show disruption of the EccB5 periplasmic assembly and increased flexibility, which highlights the importance of MycP5 for complex integrity. Beneath the EccB5–MycP5 chamber, dimers of the EccC5 ATPase assemble into three bundles of four transmembrane helices each, which together seal the potential central secretion channel. Individual cytoplasmic EccC5 domains adopt two distinctive conformations that probably reflect different secretion states. Our work suggests a previously undescribed mechanism of protein transport and provides a structural scaffold to aid in the development of drugs against this major human pathogen.

DOI: 10.1038/s41586-021-03517-z

Source: https://www.nature.com/articles/s41586-021-03517-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html