Lipid flipping in the omega-3 fatty-acid transporter

Chi Nguyen; Hsiang-Ting Lei; Louis Tung Faat Lai; Marc J Gallenito; Xuelang Mu; Doreen Matthies; Tamir Gonen

doi:10.1038/s41467-023-37702-7

Lipid flipping in the omega-3 fatty-acid transporter

Nat Commun. 2023 May 8;14(1):2571. doi: 10.1038/s41467-023-37702-7.

Authors

Chi Nguyen^#^{1

2}, Hsiang-Ting Lei^#^{1

3}, Louis Tung Faat Lai^#⁴, Marc J Gallenito^{1

2}, Xuelang Mu^{1

2

5}, Doreen Matthies^{6

7}, Tamir Gonen^{8

9

10

11}

Affiliations

¹ Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA.
² Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, 90095, USA.
³ Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA, 20147, USA.
⁴ 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.
⁵ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁶ Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA, 20147, USA. doreen.matthies@nih.gov.
⁷ 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.
⁸ Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA. tgonen@g.ucla.edu.
⁹ Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, 90095, USA. tgonen@g.ucla.edu.
¹⁰ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA. tgonen@g.ucla.edu.
¹¹ Departments of Physiology, University of California Los Angeles, Los Angeles, CA, 90095, USA. tgonen@g.ucla.edu.

^# Contributed equally.

Abstract

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.

Publication types

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

MeSH terms

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

Substances

Fatty Acids, Omega-3
Symporters
Membrane Transport Proteins
Docosahexaenoic Acids
Lysophosphatidylcholines

Abstract

Publication types

MeSH terms

Substances

Grants and funding