8d2t
Zebrafish MFSD2A isoform B in inward open ligand-free conformationZebrafish MFSD2A isoform B in inward open ligand-free conformation
Structural highlights
FunctionNLS1B_DANRE Sodium-dependent lysophosphatidylcholine (LPC) symporter, which plays an essential role for blood-brain barrier formation and function. Specifically expressed in endothelium of the blood-brain barrier of micro-vessels and transports LPC into the brain. Transport of LPC is essential because it constitutes the major mechanism by which docosahexaenoic acid (DHA), an omega-3 fatty acid that is essential for normal brain growth and cognitive function, enters the brain. Transports LPC carrying long-chain fatty acids such LPC oleate and LPC palmitate with a minimum acyl chain length of 14 carbons. Does not transport docosahexaenoic acid in unesterified fatty acid.[UniProtKB:Q9DA75] Publication Abstract from PubMedMfsd2a 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 alpha-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. Lipid flipping in the omega-3 fatty-acid transporter.,Nguyen C, Lei HT, Lai LTF, Gallenito MJ, Mu X, Matthies D, Gonen T Nat Commun. 2023 May 8;14(1):2571. doi: 10.1038/s41467-023-37702-7. PMID:37156797[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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