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Lipid flipping in the omega-3 fatty-acid transporter

Author

Listed:
  • Chi Nguyen

    (University of California Los Angeles
    University of California Los Angeles)

  • Hsiang-Ting Lei

    (University of California Los Angeles
    Howard Hughes Medical Institute)

  • Louis Tung Faat Lai

    (National Institutes of Health)

  • Marc J. Gallenito

    (University of California Los Angeles
    University of California Los Angeles)

  • Xuelang Mu

    (University of California Los Angeles
    University of California Los Angeles
    University of California, Los Angeles)

  • Doreen Matthies

    (Howard Hughes Medical Institute
    National Institutes of Health)

  • Tamir Gonen

    (University of California Los Angeles
    University of California Los Angeles
    University of California, Los Angeles
    University of California Los Angeles)

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.

Suggested Citation

  • Chi Nguyen & Hsiang-Ting Lei & Louis Tung Faat Lai & Marc J. Gallenito & Xuelang Mu & Doreen Matthies & Tamir Gonen, 2023. "Lipid flipping in the omega-3 fatty-acid transporter," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37702-7
    DOI: 10.1038/s41467-023-37702-7
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    1. Thiet M. Vu & Ayako-Nakamura Ishizu & Juat Chin Foo & Xiu Ru Toh & Fangyu Zhang & Ding Ming Whee & Federico Torta & Amaury Cazenave-Gassiot & Takayoshi Matsumura & Sangho Kim & Sue-Anne E. S. Toh & To, 2017. "Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets," Nature, Nature, vol. 550(7677), pages 524-528, October.
    2. Rosemary J. Cater & Geok Lin Chua & Satchal K. Erramilli & James E. Keener & Brendon C. Choy & Piotr Tokarz & Cheen Fei Chin & Debra Q. Y. Quek & Brian Kloss & Joseph G. Pepe & Giacomo Parisi & Bernic, 2021. "Structural basis of omega-3 fatty acid transport across the blood–brain barrier," Nature, Nature, vol. 595(7866), pages 315-319, July.
    3. Ayal Ben-Zvi & Baptiste Lacoste & Esther Kur & Benjamin J. Andreone & Yoav Mayshar & Han Yan & Chenghua Gu, 2014. "Mfsd2a is critical for the formation and function of the blood–brain barrier," Nature, Nature, vol. 509(7501), pages 507-511, May.
    4. Long N. Nguyen & Dongliang Ma & Guanghou Shui & Peiyan Wong & Amaury Cazenave-Gassiot & Xiaodong Zhang & Markus R. Wenk & Eyleen L. K. Goh & David L. Silver, 2014. "Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid," Nature, Nature, vol. 509(7501), pages 503-506, May.
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