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PreprintCited by 1Drug Transport and Resistance MechanismsTuberculosis Research and EpidemiologyLipid Membrane Structure and Behavior

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Structural basis for triacylglyceride extraction from mycobacterial inner membrane by MFS transporter Rv1410

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Remm, Sille, De Vecchis, Dario, Schöppe, Jendrik, Hutter, Cedric A.J., Gonda, Imre, Hohl, Michael, Newstead, Simon, Schäfer, Lars V., Seeger, Markus A.·2023·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2023.01.25.525346

Preprint — published as 10.1038/s41467-023-42073-0

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Abstract

Mycobacterium tuberculosis is protected from antibiotic therapy by a multi-layered hydrophobic cell envelope. Major facilitator superfamily (MFS) transporter Rv1410 and the periplasmic lipoprotein LprG are involved in transport of triacylglycerides (TAGs) that seal the mycomembrane. Here, we report a 2.7 Å structure of a mycobacterial Rv1410 homologue, which adopts an outward-facing conformation and exhibits unusual transmembrane helix 11 and 12 extensions that protrude ∼20 Å into the periplasm. A small, very hydrophobic cavity suitable for lipid transport is constricted by a unique and functionally important ion-lock likely involved in proton coupling. Combining mutational analyses and MD simulations, we propose that TAGs are extracted from the core of the inner membrane into the central cavity via lateral clefts present in the inward-facing conformation. The periplasmic helix extensions are crucial for lifting TAGs away from the membrane plane and channeling them into the lipid binding pocket of LprG.

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Metadata

Authors
Remm, S., De Vecchis, D., Schöppe, J., Hutter, C. A. J., Gonda, I., Hohl, M., Newstead, S., Schäfer, L. V., & Seeger, M. A.
Affiliations
  • University of Zurich (CH)
  • Novo Nordisk (Denmark) (DK)
  • University of Oxford (GB)
  • Ruhr University Bochum (DE)
Corresponding author
Seeger, Markus A.
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2023-01-25
DOI
10.1101/2023.01.25.525346
OpenAlex
W4318028414
Cited by
1
References
1
Citations by year
2024: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nd
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
Universität Zürich
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords
major facilitator superfamily transporter, Mycobacterium tuberculosis, mycomembrane, transporter structure, outward-facing conformation, inward-facing conformation, proton-coupled transport, lipid transport

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