MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)11241-11246
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume166
Issue number23
DOIs
StatePublished - Jan 1 2019

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Membrane Proteins
Lipids
Cord Factors
Mycolic Acids
Cell Wall
Mycobacterium smegmatis
Bacterial Proteins
Peptidoglycan
Microbial Drug Resistance
trehalose monomycolate
phosphatidylethanolamine
Mycobacterium tuberculosis
Virulence
Mass Spectrometry
Fatty Acids
Ligands
Proteins

Keywords

  • Cell-wall biogenesis
  • MmpL3 transporter
  • Mycobacterial membrane protein Large
  • Native mass spectrometry
  • X-ray crystallography

ASJC Scopus subject areas

  • General

Cite this

MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine. / Su, Chih Chia; Klenotic, Philip A.; Bolla, Jani Reddy; Purdy, Georgiana; Robinson, Carol V.; Yu, Edward W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 166, No. 23, 01.01.2019, p. 11241-11246.

Research output: Contribution to journalArticle

Su, Chih Chia ; Klenotic, Philip A. ; Bolla, Jani Reddy ; Purdy, Georgiana ; Robinson, Carol V. ; Yu, Edward W. / MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 166, No. 23. pp. 11241-11246.
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