Lipid flipping in the omega-3 fatty-acid transporter.

Fatty Acids, Omega-3 Symporters / metabolism Membrane Transport Proteins / metabolism Blood-Brain Barrier / metabolism Biological Transport Docosahexaenoic Acids Lysophosphatidylcholines / chemistry

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
08 05 2023
Historique:
received: 22 12 2022
accepted: 28 03 2023
medline: 10 5 2023
pubmed: 9 5 2023
entrez: 8 5 2023
Statut: epublish

Résumé

Mfsd2a is the transporter for docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral and motor dysfunctions to microcephaly. Mfsd2a transports long-chain unsaturated fatty-acids, including DHA and α-linolenic acid (ALA), that are attached to the zwitterionic lysophosphatidylcholine (LPC) headgroup. Even with the recently determined structures of Mfsd2a, the molecular details of how this transporter performs the energetically unfavorable task of translocating and flipping lysolipids across the lipid bilayer remains unclear. Here, we report five single-particle cryo-EM structures of Danio rerio Mfsd2a (drMfsd2a): in the inward-open conformation in the ligand-free state and displaying lipid-like densities modeled as ALA-LPC at four distinct positions. These Mfsd2a snapshots detail the flipping mechanism for lipid-LPC from outer to inner membrane leaflet and release for membrane integration on the cytoplasmic side. These results also map Mfsd2a mutants that disrupt lipid-LPC transport and are associated with disease.

Identifiants

DOI: 10.1038/s41467-023-37702-7 PMID: 37156797 PMC: PMC10167227
pubmed: 37156797
doi: 10.1038/s41467-023-37702-7
pii: 10.1038/s41467-023-37702-7
pmc: PMC10167227
doi:

Substances chimiques

Fatty Acids, Omega-3 0
Symporters 0
Membrane Transport Proteins 0
Docosahexaenoic Acids 25167-62-8
Lysophosphatidylcholines 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

2571

Subventions

Organisme : Intramural NIH HHS
ID : ZIA HD008998
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM136508
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States

Informations de copyright

© 2023. The Author(s).

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Auteurs

Chi Nguyen (C)

Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, 90095, USA.

Hsiang-Ting Lei (HT)

Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA, 20147, USA.
ORCID: 0000-0002-9444-888X

Louis Tung Faat Lai (LTF)

Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
ORCID: 0000-0003-1413-7035

Marc J Gallenito (MJ)

Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, 90095, USA.

Xuelang Mu (X)

Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

Doreen Matthies (D)

Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA, 20147, USA. doreen.matthies@nih.gov.
Unit on Structural Biology, Division of Basic and Translational Biophysics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA. doreen.matthies@nih.gov.
ORCID: 0000-0001-9221-4484

Tamir Gonen (T)

Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA. tgonen@g.ucla.edu.
Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, 90095, USA. tgonen@g.ucla.edu.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA. tgonen@g.ucla.edu.
Departments of Physiology, University of California Los Angeles, Los Angeles, CA, 90095, USA. tgonen@g.ucla.edu.
ORCID: 0000-0002-9254-4069

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Classifications MeSH

questionsmedicales.fr › Lipides › Huiles › Huiles de poisson › Acides gras omega-3 › Lipid flipping in the omega-3 fatty-acid transporter.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Pompes ioniques › Symporteurs › Lipid flipping in the omega-3 fatty-acid transporter.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Lipid flipping in the omega-3 fatty-acid transporter.
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Barrière hémato-encéphalique › Lipid flipping in the omega-3 fatty-acid transporter.
questionsmedicales.fr › Métabolisme › Transport biologique › Lipid flipping in the omega-3 fatty-acid transporter.
questionsmedicales.fr › Lipides › Huiles › Huiles de poisson › Acides gras omega-3 › Acide docosahexaénoïque › Lipid flipping in the omega-3 fatty-acid transporter.
questionsmedicales.fr › Lipides › Lipides membranaires › Phospholipides › Glycérophosphate › Acides phosphatidiques › Lysophospholipides › Lysolécithine › Lipid flipping in the omega-3 fatty-acid transporter.