7n98
Cryo-EM structure of MFSD2ACryo-EM structure of MFSD2A
Structural highlights
Function[NLS1_MOUSE] Sodium-dependent lysophosphatidylcholine (LPC) symporter, which plays an essential role for blood-brain barrier formation and function (PubMed:24828044, PubMed:24828040). 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 (PubMed:24828044). Specifically required for blood-brain barrier formation and function, probably by mediating lipid transport. Not required for central nervous system vascular morphogenesis (PubMed:24828040). Acts as a transporter for tunicamycin, an inhibitor of asparagine-linked glycosylation.[1] [2] [3] [4] Publication Abstract from PubMedMFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain(1,2), which is crucial for the development and performance of the brain(3). Mutations that affect MFSD2A cause microcephaly syndromes(4,5). The ability of MFSD2A to transport lipid is also a key mechanism that underlies its function as an inhibitor of transcytosis to regulate the blood-brain barrier(6,7). Thus, MFSD2A represents an attractive target for modulating the permeability of the blood-brain barrier for drug delivery. Here we report the cryo-electron microscopy structure of mouse MFSD2A. Our structure defines the architecture of this important transporter, reveals its unique extracellular domain and uncovers its substrate-binding cavity. The structure-together with our functional studies and molecular dynamics simulations-identifies a conserved sodium-binding site, reveals a potential lipid entry pathway and helps to rationalize MFSD2A mutations that underlie microcephaly syndromes. These results shed light on the critical lipid transport function of MFSD2A and provide a framework to aid in the design of specific modulators for therapeutic purposes. Structure and mechanism of blood-brain-barrier lipid transporter MFSD2A.,Wood CAP, Zhang J, Aydin D, Xu Y, Andreone BJ, Langen UH, Dror RO, Gu C, Feng L Nature. 2021 Aug;596(7872):444-448. doi: 10.1038/s41586-021-03782-y. Epub 2021, Aug 4. PMID:34349262[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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