National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM132120
United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)
MH12564
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM128624
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM117372
United States
National Research Foundation (NRF, Singapore)
NRF-NRFI2017-05
Singapore
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM116799
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM103310
United States
Citation
Journal: Nature / Year: 2021 Title: Structural basis of omega-3 fatty acid transport across the blood-brain barrier. Authors: 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 / ...Authors: 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 / Filippo Mancia / 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 sources. This nutrient ...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 sources. 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 manner. 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.
History
Deposition
Apr 20, 2021
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Header (metadata) release
Jun 16, 2021
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Map release
Jun 16, 2021
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Update
Jul 28, 2021
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Current status
Jul 28, 2021
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
EMPIAR-10698 (Title: Structural basis of ω-3 fatty acid transport across the blood-brain barrier Data size: 3.9 TB Data #1: MFSD2A_GG_compled with 2AG3 Fab and LPC-18:3 [micrographs - multiframe])
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