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

Autor: Martinez-Molledo M; Membrane Protein Mechanisms Group, European Institute of Chemistry and Biology, University of Bordeaux, CNRS-UMR5234, Bordeaux, France.; Membrane Protein Mechanisms Unit, Institut Pasteur, Paris, France., Nji E; Membrane Protein Mechanisms Group, European Institute of Chemistry and Biology, University of Bordeaux, CNRS-UMR5234, Bordeaux, France., Reyes N; Membrane Protein Mechanisms Group, European Institute of Chemistry and Biology, University of Bordeaux, CNRS-UMR5234, Bordeaux, France. nicolas.reyes@u-bordeaux.fr.; Membrane Protein Mechanisms Unit, Institut Pasteur, Paris, France. nicolas.reyes@u-bordeaux.fr.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2022 Jun; Vol. 29 (6), pp. 604-612. Date of Electronic Publication: 2022 Jun 16.
DOI: 10.1038/s41594-022-00786-8
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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