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Title: Crystal structure of the N-terminal domain of EccA1 ATPase from the ESX-1 secretion system of Mycobacterium tuberculosis

Authors:
; ;  [1]
  1. (Kentucky)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
DOE - BASIC ENERGY SCIENCESNIHNIGMS
OSTI Identifier:
1140057
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proteins; Journal Volume: 82; Journal Issue: (1) ; 01, 2014
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Wagner, Jonathan M., Evans, Timothy J., and Korotkov, Konstantin V. Crystal structure of the N-terminal domain of EccA1 ATPase from the ESX-1 secretion system of Mycobacterium tuberculosis. United States: N. p., 2014. Web. doi:10.1002/prot.24351.
Wagner, Jonathan M., Evans, Timothy J., & Korotkov, Konstantin V. Crystal structure of the N-terminal domain of EccA1 ATPase from the ESX-1 secretion system of Mycobacterium tuberculosis. United States. doi:10.1002/prot.24351.
Wagner, Jonathan M., Evans, Timothy J., and Korotkov, Konstantin V. Fri . "Crystal structure of the N-terminal domain of EccA1 ATPase from the ESX-1 secretion system of Mycobacterium tuberculosis". United States. doi:10.1002/prot.24351.
@article{osti_1140057,
title = {Crystal structure of the N-terminal domain of EccA1 ATPase from the ESX-1 secretion system of Mycobacterium tuberculosis},
author = {Wagner, Jonathan M. and Evans, Timothy J. and Korotkov, Konstantin V.},
abstractNote = {},
doi = {10.1002/prot.24351},
journal = {Proteins},
number = (1) ; 01, 2014,
volume = 82,
place = {United States},
year = {Fri Sep 05 00:00:00 EDT 2014},
month = {Fri Sep 05 00:00:00 EDT 2014}
}
  • Cited by 5
  • 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 in this paper, we report the crystal structure of a PE-PPE heterodimer bound to ESX secretion-associated protein G (EspG), whichmore » 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. Furthermore, 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.« less
  • Mycobacterium tuberculosis encodes five gene clusters (ESX-1 to ESX-5) for Type VII protein secretion systems that are implicated in mycobacterial pathogenicity. Substrates for the secretion apparatus are encoded within the gene clusters and in additional loci that lack the components of the secretion apparatus. The best characterized substrates are the ESX complexes, 1:1 heterodimers of ESAT-6 and CFP-10, the prototypical member that has been shown to be essential for Mycobacterium tuberculosis pathogenesis. We have determined the structure of EsxRS, a homolog of EsxGH of the ESX-3 gene cluster, at 1.91 {angstrom} resolution. The EsxRS structure is composed of two four-helixmore » bundles resulting from the 3D domain swapping of the C-terminal domain of EsxS, the CFP-10 homolog. The four-helix bundles at the extremities of the complex have a similar architecture to the structure of ESAT-6 {center_dot} CFP-10 (EsxAB) of ESX-1, but in EsxRS a hinge loop linking the {alpha}-helical domains of EsxS undergoes a loop-to-helix transition that creates the domain swapped EsxRS tetramer. Based on the atomic structure of EsxRS and existing biochemical data on ESX complexes, we propose that higher order ESX oligomers may increase avidity of ESX binding to host receptor molecules or, alternatively, the conformational change that creates the domain swapped structure may be the basis of ESX complex dissociation that would free ESAT-6 to exert a cytotoxic effect.« less