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

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, Bernice H. Wong, Oliver B. Clarke, Michael T. Marty, Anthony A. Kossiakoff, George Khelashvili (), David L. Silver () and Filippo Mancia ()
Additional contact information
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
Michael T. Marty: University of Arizona
Anthony A. Kossiakoff: University of Chicago
George Khelashvili: Cornell University
David L. Silver: Duke-NUS Medical School
Filippo Mancia: Columbia University

Nature, 2021, vol. 595, issue 7866, 315-319

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03650-9

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