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Structural basis of omega-3 fatty acid transport across the blood–brain barrier

Author

Listed:
  • Rosemary J. Cater

    (Columbia University)

  • Geok Lin Chua

    (Duke-NUS Medical School)

  • Satchal K. Erramilli

    (University of Chicago)

  • James E. Keener

    (University of Arizona)

  • Brendon C. Choy

    (Columbia University)

  • Piotr Tokarz

    (University of Chicago)

  • Cheen Fei Chin

    (Duke-NUS Medical School)

  • Debra Q. Y. Quek

    (Duke-NUS Medical School)

  • Brian Kloss

    (New York Structural Biology Center)

  • Joseph G. Pepe

    (Columbia University)

  • Giacomo Parisi

    (Columbia University)

  • Bernice H. Wong

    (Duke-NUS Medical School)

  • Oliver B. Clarke

    (Columbia University
    Columbia University Irving Medical Center)

  • Michael T. Marty

    (University of Arizona)

  • Anthony A. Kossiakoff

    (University of Chicago)

  • George Khelashvili

    (Cornell University
    Cornell University)

  • David L. Silver

    (Duke-NUS Medical School)

  • Filippo Mancia

    (Columbia University)

Abstract

Docosahexaenoic acid is an omega-3 fatty acid that is essential for neurological development and function, and it is supplied to the brain and eyes predominantly from dietary sources1–6. This nutrient is transported across the blood–brain and blood–retina barriers in the form of lysophosphatidylcholine by major facilitator superfamily domain containing 2A (MFSD2A) in a Na+-dependent manner7,8. Here we present the structure of MFSD2A determined using single-particle cryo-electron microscopy, which reveals twelve transmembrane helices that are separated into two pseudosymmetric domains. The transporter is in an inward-facing conformation and features a large amphipathic cavity that contains the Na+-binding site and a bound lysolipid substrate, which we confirmed using native mass spectrometry. Together with our functional analyses and molecular dynamics simulations, this structure reveals details of how MFSD2A interacts with substrates and how Na+-dependent conformational changes allow for the release of these substrates into the membrane through a lateral gate. Our work provides insights into the molecular mechanism by which this atypical major facility superfamily transporter mediates the uptake of lysolipids into the brain, and has the potential to aid in the delivery of neurotherapeutic agents.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:595:y:2021:i:7866:d:10.1038_s41586-021-03650-9
    DOI: 10.1038/s41586-021-03650-9
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    Citations

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    Cited by:

    1. Anca-Denise Ciută & Kamil Nosol & Julia Kowal & Somnath Mukherjee & Ana S. Ramírez & Bruno Stieger & Anthony A. Kossiakoff & Kaspar P. Locher, 2023. "Structure of human drug transporters OATP1B1 and OATP1B3," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Shana Bergman & Rosemary J. Cater & Ambrose Plante & Filippo Mancia & George Khelashvili, 2023. "Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Shuhui Wang & Kun Wang & Kangkang Song & Zon Weng Lai & Pengfei Li & Dongying Li & Yajie Sun & Ye Mei & Chen Xu & Maofu Liao, 2024. "Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. 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.
    5. Elisabeth Lambert & Ahmad Reza Mehdipour & Alexander Schmidt & Gerhard Hummer & Camilo Perez, 2022. "Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Sille Remm & Dario Vecchis & Jendrik Schöppe & Cedric A. J. Hutter & Imre Gonda & Michael Hohl & Simon Newstead & Lars V. Schäfer & Markus A. Seeger, 2023. "Structural basis for triacylglyceride extraction from mycobacterial inner membrane by MFS transporter Rv1410," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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