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Atomic dissection of type VII secretion systems from pathogenic mycobacteria

Project description

Pathogenesis and the secretion systems of Mycobacterium tuberculosis

An estimated one quarter of the world’s population is infected with Mycobacterium tuberculosis (Mtb). Mtb is highly efficient as a pathogen due to its distinct and hydrophobic outer membrane (OM) and type VII secretion systems (T7SSs). There are five T7SSs that perform different functions such as immunomodulation, virulence and nutrient uptake, and four conserved membrane components which form a hexameric inner membrane complex, with a fifth transiently interacting membrane component called MycP. The EU-funded CryoMyco project aims to elucidate the mechanism of secretion through the Mtb cell envelope by deciphering the high-resolution structure of the hexameric T7SS membrane complex as well as the molecular and structural mechanisms behind the OM translocation process.

Objective

Tuberculosis (TB) is a global disease. With over 1.6 million deaths in 2017 alone and an estimated one quarter of the world’s population infected with Mycobacterium tuberculosis (Mtb), the etiological agent, TB is found throughout the world. Mtb is highly successful as a pathogen, in part due to its distinct and hydrophobic outer membrane (OM) and its type VII secretion systems (T7SSs). Although critical for the success of Mtb as a pathogen, the structure and mechanism of T7SSs are still poorly understood. In Mtb, five T7SSs (ESX-1 to 5) perform diverse functions such as immunomodulation, virulence, uptake of nutrients and iron. In T7SSs, four conserved membrane components, EccB/C/D/E assemble into a hexameric inner membrane complex, with a fifth transiently interacting membrane component, MycP. We have previously shown a low resolution, hexameric structure of the EccB/C/D/E membrane complex and recently two models of a dimeric subcomplex have been published. However, little is known on the structure of the entire core complex (including MycP), what is the secretion pore and how is it gated, or how secretion takes place through the OM, making this research proposal timely and necessary. The aim of this fellowship is to elucidate the underlying mechanism of secretion through the diderm cell envelope by: 1 - Elucidating the high-resolution structure of the hexameric T7SS membrane complex of Mtb. 2 - Investigate the molecular and structural mechanisms behind the OM translocation process. The results stemming from this proposal have the potential to aid and steer structure-based drug designs against Mtb. The host lab has pioneered cryo-EM of secretion systems and has state-of-the-art infrastructure and know-how that will provide the fellow with the best possible training and chances of success. With appropriate measures put in place, this project will drive forward mycobacterial research and will serve as a starting platform for identifying new possible drug targets.

Keywords

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Coordinator

UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Net EU contribution
€ 174 806,40
Address
Martinistrasse 52
20251 Hamburg
Germany

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Region
Hamburg Hamburg Hamburg
Activity type
Higher or Secondary Education Establishments
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Other funding
€ 0,00