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TitleLipid flipping in the omega-3 fatty-acid transporter.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 2571, Year 2023
Publish dateMay 8, 2023
AuthorsChi Nguyen / Hsiang-Ting Lei / Louis Tung Faat Lai / Marc J Gallenito / Xuelang Mu / Doreen Matthies / Tamir Gonen /
PubMed AbstractMfsd2a is the transporter for docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral and motor dysfunctions ...Mfsd2a is the transporter for docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral and motor dysfunctions to microcephaly. Mfsd2a transports long-chain unsaturated fatty-acids, including DHA and α-linolenic acid (ALA), that are attached to the zwitterionic lysophosphatidylcholine (LPC) headgroup. Even with the recently determined structures of Mfsd2a, the molecular details of how this transporter performs the energetically unfavorable task of translocating and flipping lysolipids across the lipid bilayer remains unclear. Here, we report five single-particle cryo-EM structures of Danio rerio Mfsd2a (drMfsd2a): in the inward-open conformation in the ligand-free state and displaying lipid-like densities modeled as ALA-LPC at four distinct positions. These Mfsd2a snapshots detail the flipping mechanism for lipid-LPC from outer to inner membrane leaflet and release for membrane integration on the cytoplasmic side. These results also map Mfsd2a mutants that disrupt lipid-LPC transport and are associated with disease.
External linksNat Commun / PubMed:37156797 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 4.1 Å
Structure data

EMDB-27148, PDB-8d2s:
Zebrafish MFSD2A isoform B in inward open ligand bound conformation
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-27149, PDB-8d2t:
Zebrafish MFSD2A isoform B in inward open ligand-free conformation
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-27150, PDB-8d2u:
Zebrafish MFSD2A isoform B in inward open ligand 1A conformation
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-27151, PDB-8d2v:
Zebrafish MFSD2A isoform B in inward open ligand 1B conformation
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-27152, PDB-8d2w:
Zebrafish MFSD2A isoform B in inward open ligand 2B conformation
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-27153, PDB-8d2x:
Zebrafish MFSD2A isoform B in inward open ligand 3C conformation
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-ZGS:
[(2~{R})-2-oxidanyl-3-[oxidanyl-[2-(trimethyl-$l^{4}-azanyl)ethoxy]phosphoryl]oxy-propyl] (9~{Z},12~{Z},15~{Z})-octadeca-9,12,15-trienoate

ChemComp-LMT:
DODECYL-BETA-D-MALTOSIDE / detergent*YM

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER

Source
  • danio rerio (zebrafish)
  • mus musculus (house mouse)
KeywordsLIPID TRANSPORT / omega-3 fatty acid / membrane protein / Fab

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