Structure of the mycobacterial ESX-5 type VII secretion system pore complex

Abstract

The ESX-5 type VII secretion system is a membrane-spanning protein complex key to the virulence of mycobacterial pathogens. However, the overall architecture of the fully assembled translocation machinery and the composition of the central secretion pore have remained unknown. Here, we present the high-resolution structure of the 2.1-megadalton ESX-5 core complex. Our structure captured a dynamic, secretion-competent conformation of the pore within a well-defined transmembrane section, sandwiched between two flexible protein layers at the cytosolic entrance and the periplasmic exit. We propose that this flexibility endows the ESX-5 machinery with large conformational plasticity required to accommodate targeted protein secretion. Compared to known secretion systems, a highly dynamic state of the pore may represent a fundamental principle of bacterial secretion machineries.

Homologous recombination between tandem paralogues drives evolution of a subset of Type VII secretion system immunity genes in firmicute bacteria

“…Following its discovery in pathogenic Mycobacteria, it has since been described in a range of other actinobacteria and in firmicutes (1)(2)(3)(4)(5). Cryo-electron microscopy studies have shown that the ESX-5 T7SS from Mycobacteria exists as a 2.3 MDa membrane complex, with a central ATPase, EccC, forming a hexameric pore (6,7). The firmicutes T7SS is only distantly related to the actinobacterial T7SSa system and has been termed T7SSb.…”

Bacterial protein secretion systems: Game of types

“…The genes in the vicinity of the gene encoding ESAT-6 [122], were proposed to represent such secretion system which was named ESX, and later coined the T7SS [123]. Genomic and biochemical studies suggested a minimal organisation of the T7SS involving the inner membrane components EccB, EccC, EccD, EccE and MycP [124–126]. In case of the M.…”

“…The genes in the vicinity of the gene encoding ESAT-6 [122], were proposed to represent such secretion system which was named ESX, and later coined the T7SS [123]. Genomic and biochemical studies suggested a minimal organisation of the T7SS involving the inner membrane components EccB, EccC, EccD, EccE and MycP [124][125][126]. In case of the M. tuberculosis ESX-5 system, the cryo-EM structure of the purified complex displays a trimer of dimers for each subunit except for EccD which is present in a total of 12 copies [127].…”

Design Principles of the Rotary Type 9 Secretion System

“…The Type 7 Secretion System (T7SS) is found in Gram positive bacteria of the genus Mycobacterium and other members of the phylum Actinobacteria. Five paralogous esx loci are found in Mycobacteria and a recent high resolution Cryo-EM structure of an Esx-5 paralog revealed the formation of an inner membrane pore ( Bunduc et al, 2020 ; Beckham et al, 2021 ; Rivera-Calzada et al, 2021 ). The Type 8 Secretion System (T8SS), widely known as the curli biogenesis pathway spans the outer membrane of Gram-negative bacteria.…”