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Supramolecular organisation and dynamics of mannosylated phosphatidylinositol lipids in the mycobacterial plasma membrane
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Brown, Chelsea M., Corey, Robin A., Grélard, Axelle , Gao, Ya, Kyo Choi, Yeol, Luna, Emanuel, Gilleron, Martine, Destainville, Nicolas, Nigou, Jérôme, Loquet, Antoine, Fullam, Elizabeth, Im, Wonpil, Stansfeld, Phillip J. and Chavent, Matthieu (2023) Supramolecular organisation and dynamics of mannosylated phosphatidylinositol lipids in the mycobacterial plasma membrane. Proceedings of the National Academy of Sciences of the United States of America, 120 (5). e2212755120. doi:10.1073/pnas.2212755120 ISSN 0027-8424.
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Official URL: https://doi.org/10.1073/pnas.2212755120
Abstract
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a disease that claims ~1.6 million lives annually. The current treatment regime is long and expensive, and missed doses contribute to drug resistance. Therefore, development of new anti-TB drugs remains one of the highest public health priorities. Mtb has evolved a complex cell envelope that represents a formidable barrier to antibiotics. The Mtb cell envelop consists of four distinct layers enriched for Mtb specific lipids and glycans. Although the outer membrane, comprised of mycolic acid esters, has been extensively studied, less is known about the plasma membrane, which also plays a critical role in impacting antibiotic efficacy. The Mtb plasma membrane has a unique lipid composition, with mannosylated phosphatidylinositol lipids (phosphatidyl-myoinositol mannosides, PIMs) comprising more than 50% of the lipids. However, the role of PIMs in the structure and function of the membrane remains elusive. Here, we used multiscale molecular dynamics (MD) simulations to understand the structure-function relationship of the PIM lipid family and decipher how they self-organize to shape the biophysical properties of mycobacterial plasma membranes. We assess both symmetric and asymmetric assemblies of the Mtb plasma membrane and compare this with residue distributions of Mtb integral membrane protein structures. To further validate the model, we tested known anti-TB drugs and demonstrated that our models agree with experimental results. Thus, our work sheds new light on the organization of the mycobacterial plasma membrane. This paves the way for future studies on antibiotic development and understanding Mtb membrane protein function.
Item Type: | Journal Article | |||||||||||||||||||||||||||||||||||||||||||||
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Subjects: | Q Science > QH Natural history Q Science > QP Physiology Q Science > QR Microbiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | |||||||||||||||||||||||||||||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Mycobacterium tuberculosis , Tuberculosis -- Microbiology , Tuberculosis -- Transmission , Cell membranes, Cell membranes -- Formation, Lipids , Molecular dynamics -- Computer simulation | |||||||||||||||||||||||||||||||||||||||||||||
Journal or Publication Title: | Proceedings of the National Academy of Sciences of the United States of America | |||||||||||||||||||||||||||||||||||||||||||||
Publisher: | National Academy of Sciences | |||||||||||||||||||||||||||||||||||||||||||||
ISSN: | 0027-8424 | |||||||||||||||||||||||||||||||||||||||||||||
Official Date: | 24 January 2023 | |||||||||||||||||||||||||||||||||||||||||||||
Dates: |
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Volume: | 120 | |||||||||||||||||||||||||||||||||||||||||||||
Number: | 5 | |||||||||||||||||||||||||||||||||||||||||||||
Article Number: | e2212755120 | |||||||||||||||||||||||||||||||||||||||||||||
DOI: | 10.1073/pnas.2212755120 | |||||||||||||||||||||||||||||||||||||||||||||
Status: | Peer Reviewed | |||||||||||||||||||||||||||||||||||||||||||||
Publication Status: | Published | |||||||||||||||||||||||||||||||||||||||||||||
Access rights to Published version: | Restricted or Subscription Access | |||||||||||||||||||||||||||||||||||||||||||||
Date of first compliant deposit: | 20 December 2022 | |||||||||||||||||||||||||||||||||||||||||||||
Date of first compliant Open Access: | 24 July 2023 | |||||||||||||||||||||||||||||||||||||||||||||
RIOXX Funder/Project Grant: |
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