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TitleStructural insights into the lysophospholipid brain uptake mechanism and its inhibition by syncytin-2.
Journal, issue, pagesNat Struct Mol Biol, Vol. 29, Issue 6, Page 604-612, Year 2022
Publish dateJun 16, 2022
AuthorsMaria Martinez-Molledo / Emmanuel Nji / Nicolas Reyes /
PubMed AbstractBrain 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 ...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.
External linksNat Struct Mol Biol / PubMed:35710838
MethodsEM (single particle)
Resolution3.6 Å
Structure data

12935

7oix

EMDB-12935, PDB-7oix:
Structure of thermostable human MFSD2A in complex with thermostable human Sync2
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / human membrane protein / MFS transporter / human endogenous retroviral protein / syncytin

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