@article{9f33adb8b69a4b5b8b7e560400954450,
title = "Structural basis of omega-3 fatty acid transport across the blood–brain barrier",
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.",
author = "Cater, {Rosemary J.} and Chua, {Geok Lin} and Erramilli, {Satchal K.} and Keener, {James E.} and Choy, {Brendon C.} and Piotr Tokarz and Chin, {Cheen Fei} and Quek, {Debra Q.Y.} and Brian Kloss and Pepe, {Joseph G.} and Giacomo Parisi and Wong, {Bernice H.} and Clarke, {Oliver B.} and Marty, {Michael T.} and Kossiakoff, {Anthony A.} and George Khelashvili and Silver, {David L.} and Filippo Mancia",
note = "Funding Information: Acknowledgements We thank members of the laboratory of F.M., Columbia Cryo-EM facility and Iowa State University Protein Facility for their assistance; and E. Kots for generating the molecular dynamics trajectory video. This work was supported by NIH grants (R35 GM132120 and R21 MH125649 to F.M., R35 GM128624 to M.T.M. and R01 GM117372 to A.A.K.) and grants from the National Research Foundation and Ministry of Health, Singapore (NRF-NRFI2017-05 and MOH-000217 to D.L.S.). R.J.C. was supported by the Simons Society of Fellows (award number 578646). G.K. is supported by the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute of Computational Biomedicine at Weill Cornell Medical College through the 1923 Fund. C.F.C. and B.H.W. are supported by the Khoo Postdoctoral Research Fellowship. Some of the work was performed at the Center for Membrane Protein Production and Analysis (COMPP{\AA}; NIH P41 GM116799 to W. A. Hendrickson), and at the National Resource for Automated Molecular Microscopy at the Simons Electron Microscopy Center (P41 GM103310), both located at the New York Structural Biology Center. Molecular dynamics simulations were performed using the Oak Ridge Leadership Computing Facility (summit allocation BIP109) at the Oak Ridge National Laboratory (supported by the Office of Science of the US Department of Energy under contract number DE-AC05-00OR22725), and computational resources of the David A. Cofrin Center for Biomedical Information at Weill Cornell Medical College. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2021",
month = jul,
day = "8",
doi = "10.1038/s41586-021-03650-9",
language = "English (US)",
volume = "595",
pages = "315--319",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7866",
}