title: Structure of a PE-PPE-EspG complex from Mycobacterium tuberculosis reveals molecular specificity of ESX protein secretion.
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.
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, CA 94143 damian.ekiert@ucsf.edu jeffery.cox@ucsf.edu.
authors.forename: Damian C
authors.initials: DC
authors.lastname: Ekiert
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, CA 94143 damian.ekiert@ucsf.edu jeffery.cox@ucsf.edu.
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Cox
mesh_terms: D020816:Amino Acid Motifs; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D058947:Bacterial Secretion Systems; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D008954:Models, Biological; D008958:Models, Molecular; D005810:Multigene Family; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; D021122:Protein Subunits
keywords: antigenic variation; host–pathogen interactions; protein secretion; tuberculosis; virulence factor