2. Academic Validation
  3. Structural basis of omega-3 fatty acid transport across the blood-brain barrier

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

  • Nature. 2021 Jul;595(7866):315-319. doi: 10.1038/s41586-021-03650-9.
Rosemary J Cater 1,  Geok Lin Chua 2,  Satchal K Erramilli 3,  James E Keener 4,  Brendon C Choy 1,  Piotr Tokarz 3,  Cheen Fei Chin 2,  Debra Q Y Quek 2,  Brian Kloss 5,  Joseph G Pepe 1,  Giacomo Parisi 1,  Bernice H Wong 2,  Oliver B Clarke 1 6,  Michael T Marty 4,  Anthony A Kossiakoff 3,  George Khelashvili 7 8,  David L Silver 9,  Filippo Mancia 10
Affiliations

Affiliations

  • 1 Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.
  • 2 Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore.
  • 3 Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
  • 4 Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.
  • 5 Center on Membrane Protein Production and Analysis, New York Structural Biology Center, New York, NY, USA.
  • 6 Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA.
  • 7 Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, NY, USA. [email protected].
  • 8 Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY, USA. [email protected].
  • 9 Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore. [email protected].
  • 10 Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA. [email protected].
PMID: 34135507 DOI: 10.1038/s41586-021-03650-9
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.

Figures