MARTINEZ-MOLLEDO, Maria; NJI, Emmanuel; REYES, Nicolas

doi:10.1038/s41594-022-00786-8

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MARTINEZ-MOLLEDO, Maria
Microbiologie Fondamentale et Pathogénicité [MFP]

NJI, Emmanuel
Microbiologie Fondamentale et Pathogénicité [MFP]

REYES, Nicolas

Microbiologie Fondamentale et Pathogénicité [MFP]

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Nature Structural and Molecular Biology. 2022-06-01, vol. 29, n° 6, p. 604-612

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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.< Réduire

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Animals

Brain

Cryoelectron Microscopy

Female

Humans

Lysophosphatidylcholines

Mammals

Membrane Transport Proteins

Pregnancy

Pregnancy Proteins

Symporters

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Structural insights into the lysophospholipid brain uptake mechanism and its inhibition by syncytin-2.

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