Open AccessStructures of the mycobacterial membrane protein MmpL3 reveal its mechanism of lipid transport
Author(s) -
ChihChia Su,
Philip A. Klenotic,
Meng Cui,
Meinan Lyu,
Christopher E. Morgan,
Edward Yu
Publication year - 2021
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001370
Subject(s) - mycobacterium smegmatis , biology , mycolic acid , cell wall , biochemistry , periplasmic space , transmembrane protein , cell membrane , atp binding cassette transporter , peptidoglycan , vesicular transport protein , trehalose , transport protein , mycobacterium , microbiology and biotechnology , transporter , membrane , vesicle , mycobacterium tuberculosis , bacteria , gene , genetics , medicine , tuberculosis , receptor , pathology , escherichia coli
The mycobacterial membrane protein large 3 (MmpL3) transporter is essential and required for shuttling the lipid trehalose monomycolate (TMM), a precursor of mycolic acid (MA)-containing trehalose dimycolate (TDM) and mycolyl arabinogalactan peptidoglycan (mAGP), in Mycobacterium species, including Mycobacterium tuberculosis and Mycobacterium smegmatis . However, the mechanism that MmpL3 uses to facilitate the transport of fatty acids and lipidic elements to the mycobacterial cell wall remains elusive. Here, we report 7 structures of the M . smegmatis MmpL3 transporter in its unbound state and in complex with trehalose 6-decanoate (T6D) or TMM using single-particle cryo-electron microscopy (cryo-EM) and X-ray crystallography. Combined with calculated results from molecular dynamics (MD) and target MD simulations, we reveal a lipid transport mechanism that involves a coupled movement of the periplasmic domain and transmembrane helices of the MmpL3 transporter that facilitates the shuttling of lipids to the mycobacterial cell wall.