Structure and dynamics of a mycobacterial type VII secretion system

Area of Science:

• Structural biology
• Microbiology
• Molecular mechanisms of disease

Background:

• Mycobacterium tuberculosis causes millions of deaths annually.
• Type VII secretion systems (T7SSs) are critical for M. tuberculosis virulence and nutrient transport.
• Understanding T7SS structure is key to developing new anti-TB drugs.

Purpose of the Study:

• To elucidate the structure of the intact T7SS inner-membrane complex (ESX-5) in M. tuberculosis.
• To understand the role of MycP5 protease in T7SS assembly and stability.
• To provide a structural basis for novel drug development against M. tuberculosis.

Main Methods:

• Cryo-electron microscopy (Cryo-EM) to determine the structure of the 2.32-MDa ESX-5 complex.
• Protease activity assays to investigate the role of MycP5.
• Comparative structural analysis of T7SS complexes with and without MycP5.

Main Results:

• The 2.32-MDa ESX-5 assembly is stabilized as a trimer of dimers by MycP5 protease.
• MycP5 forms a trimer that caps a periplasmic chamber involving EccB5 dimers, suggesting a secretion conduit.
• EccC5 ATPase dimers assemble beneath the chamber, sealing the secretion channel and exhibiting distinct conformations.

Conclusions:

• MycP5 is essential for the integrity and stability of the T7SS ESX-5 complex.
• The study proposes a novel mechanism for protein secretion and processing via the T7SS.
• The determined structure provides a scaffold for designing targeted therapeutics against M. tuberculosis.