MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine

Su, Chih-Chia; Klenotic, Philip A.; Bolla, Jani Reddy; Purdy, Georgiana E.; Robinson, Carol V.; Yu, Edward W.

doi:10.1073/pnas.1901346116

Title: MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine

Journal Article · 21 May 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1901346116 · OSTI ID:1531017

Su, Chih-Chia ^[1]; Klenotic, Philip A. ^[1];

^[2]; Purdy, Georgiana E. ^[3];

^[2];

^[1]

Case Western Reserve Univ., Cleveland, OH (United States)
Univ. of Oxford (United Kingdom)
Oregon Health & Science Univ., Portland, OR (United States)

The cell envelope of Mycobacterium tuberculosis is notable for the abundance of mycolic acids (MAs), essential to mycobacterial viability, and of other species-specific lipids. The mycobacterial cell envelope is extremely hydrophobic, which contributes to virulence and antibiotic resistance. However, exactly how fatty acids and lipidic elements are transported across the cell envelope for cell-wall biosynthesis is unclear. Mycobacterial membrane protein Large 3 (MmpL3) is essential and required for transport of trehalose monomycolates (TMMs), precursors of MA-containing trehalose dimycolates (TDM) and mycolyl arabinogalactan peptidoglycan, but the exact function of MmpL3 remains elusive. Here, we report a crystal structure of Mycobacterium smegmatis MmpL3 at a resolution of 2.59 Å, revealing a monomeric molecule that is structurally distinct from all known bacterial membrane proteins. A previously unknown MmpL3 ligand, phosphatidylethanolamine (PE), was discovered inside this transporter. We also show, via native mass spectrometry, that MmpL3 specifically binds both TMM and PE, but not TDM, in the micromolar range. These observations provide insight into the function of MmpL3 and suggest a possible role for this protein in shuttling a variety of lipids to strengthen the mycobacterial cell wall.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH)

OSTI ID:: 1531017

Report Number(s):: AC02-06CH11357

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, Issue 23; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 80 works

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59 BASIC BIOLOGICAL SCIENCES
mycobacterial membrane protein Large
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X-ray crystallography
native mass spectrometry

Title: MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine

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