Structures of the mycobacterial membrane protein MmpL3 reveal its mechanism of lipid transport

Su, Chih-Chia; Klenotic, Philip A.; Cui, Meng; Lyu, Meinan; Morgan, Christopher E.; Yu, Edward W.

doi:10.1371/journal.pbio.3001370

Title: Structures of the mycobacterial membrane protein MmpL3 reveal its mechanism of lipid transport

Journal Article · Thu Aug 12 00:00:00 EDT 2021 · PLoS Biology (Online)

DOI:https://doi.org/10.1371/journal.pbio.3001370· OSTI ID:1903928

^[1];

^[2]; Lyu, Meinan ^[1]; Morgan, Christopher E. ^[1];

^[1]

Case Western Reserve University, Cleveland, OH (United States)
Northeastern University, Boston, MA (United States)

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.

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Research Organization:: Case Western Reserve Univ., Cleveland, OH (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Cancer Institute (NCI)

Grant/Contract Number:: AC05-76RL01830; R01AI145069; HSSN261200800001E; U24GM129547

OSTI ID:: 1903928

Journal Information:: PLoS Biology (Online), Vol. 19, Issue 8; ISSN 1545-7885

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
electron cryo-microscopy
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membrane proteins
mycobacterium tuberculosis
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molecular dynamics
trehalose
crystal structure

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