Structure of EspB from the ESX-1 type VII secretion system and insights into its export mechanism

TY - JOUR

T1 - Structure of EspB from the ESX-1 type VII secretion system and insights into its export mechanism

AU - Solomonson, Matthew

AU - Setiaputra, Dheva

AU - Makepeace, Karl A T

AU - Lameignere, Emilie

AU - Petrotchenko, Evgeniy V

AU - Conrady, Deborah G

AU - Bergeron, Julien R

AU - Vuckovic, Marija

AU - DiMaio, Frank

AU - Borchers, Christoph H

AU - Yip, Calvin K

AU - Strynadka, Natalie C J

N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/3/3

Y1 - 2015/3/3

N2 - Mycobacterium tuberculosis (Mtb) uses the ESX-1 type VII secretion system to export virulence proteins across its lipid-rich cell wall, which helps permeabilize the host's macrophage phagosomal membrane, facilitating the escape and cell-to-cell spread of Mtb. ESX-1 membranolytic activity depends on a set of specialized secreted Esp proteins, the structure and specific roles of which are not currently understood. Here, we report the X-ray and electron microscopic structures of the ESX-1-secreted EspB. We demonstrate that EspB adopts a PE/PPE-like fold that mediates oligomerization with apparent heptameric symmetry, generating a barrel-shaped structure with a central pore that we propose contributes to the macrophage killing functions of EspB. Our structural data also reveal unexpected direct interactions between the EspB bipartite secretion signal sequence elements that form a unified aromatic surface. These findings provide insight into how specialized proteins encoded within the ESX-1 locus are targeted for secretion, and for the first time indicate an oligomerization-dependent role for Esp virulence factors.

AB - Mycobacterium tuberculosis (Mtb) uses the ESX-1 type VII secretion system to export virulence proteins across its lipid-rich cell wall, which helps permeabilize the host's macrophage phagosomal membrane, facilitating the escape and cell-to-cell spread of Mtb. ESX-1 membranolytic activity depends on a set of specialized secreted Esp proteins, the structure and specific roles of which are not currently understood. Here, we report the X-ray and electron microscopic structures of the ESX-1-secreted EspB. We demonstrate that EspB adopts a PE/PPE-like fold that mediates oligomerization with apparent heptameric symmetry, generating a barrel-shaped structure with a central pore that we propose contributes to the macrophage killing functions of EspB. Our structural data also reveal unexpected direct interactions between the EspB bipartite secretion signal sequence elements that form a unified aromatic surface. These findings provide insight into how specialized proteins encoded within the ESX-1 locus are targeted for secretion, and for the first time indicate an oligomerization-dependent role for Esp virulence factors.

KW - Amino Acid Sequence

KW - Bacterial Proteins/chemistry

KW - Bacterial Secretion Systems/chemistry

KW - Biological Transport

KW - Crystallography, X-Ray

KW - Hydrogen Bonding

KW - Hydrophobic and Hydrophilic Interactions

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Mycobacterium smegmatis/chemistry

KW - Mycobacterium tuberculosis/chemistry

KW - Protein Structure, Quaternary

KW - Protein Structure, Secondary

U2 - 10.1016/j.str.2015.01.002

DO - 10.1016/j.str.2015.01.002

M3 - Article

C2 - 25684576

SN - 0969-2126

VL - 23

SP - 571

EP - 583

JO - Structure

JF - Structure

IS - 3

ER -