Structure of a PE-PPE-EspG complex from mycobacterium tuberculosis reveals molecular specificity of ESX protein secretion

Damian C. Ekiert, Jeffery S. Cox, Scott J. Hultgren

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)14758-14763
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number41
DOIs
StatePublished - Oct 14 2014

Keywords

  • Antigenic variation
  • Host-pathogen interactions
  • Protein secretion
  • Tuberculosis
  • Virulence factor

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