Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 29, Issue 6, Pages 604-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41594-022-00786-8
Keywords
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Funding
- French National Research Agency [ANR-10-INSB-04]
- European Research Council (ERC) under European Union Horizon 2020 Program [771965]
- IDEX Senior Chair of Bordeaux University
- Region Nouvelle-Aquitaine [8166910]
- European Research Council (ERC) [771965] Funding Source: European Research Council (ERC)
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This study reports the structure of the human MFSD2A-SYNC2 complex and reveals its importance in brain and placenta development and function. Additionally, SYNC2 acts as an inhibitor of MFSD2A transport, providing a new strategy for delivering therapeutic macromolecules across the blood-brain barrier.
Brain development and function require uptake of essential omega-3 fatty acids in the form of lysophosphatidylcholine via major-facilitator superfamily transporter MFSD2A, a potential pharmaceutical target to modulate blood-brain barrier (BBB) permeability. MFSD2A is also the receptor of endogenous retroviral envelope syncytin-2 (SYNC2) in human placenta, where it mediates cell-cell fusion and formation of the maternal-fetal interface. Here, we report a cryo-electron microscopy structure of the human MFSD2A-SYNC2 complex that reveals a large hydrophobic cavity in the transporter C-terminal domain to occlude long aliphatic chains. The transporter architecture suggests an alternating-access transport mechanism for lipid substrates in mammalian MFS transporters. SYNC2 establishes an extensive binding interface with MFSD2A, and a SYNC2-soluble fragment acts as a long-sought-after inhibitor of MFSD2A transport. Our work uncovers molecular mechanisms important to brain and placenta development and function, and SYNC2-mediated inhibition of MFSD2A transport suggests strategies to aid delivery of therapeutic macromolecules across the BBB.
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