Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Nat Commun. 2023 May 8;14(1):2571. doi: 10.1038/s41467-023-37702-7.
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.
Mfsd2a 是一种跨血脑屏障（BBB）的二十二碳六烯酸（DHA）等 ω-3 脂肪酸的转运蛋白。Mfsd2a 的缺陷与行为和运动功能障碍到小头症等疾病有关。Mfsd2a 转运长链不饱和脂肪酸，包括 DHA 和 α-亚麻酸（ALA），它们附着在两性离子溶血磷脂酰胆碱（LPC）的头基上。即使有了最近确定的 Mfsd2a 结构，这种转运蛋白如何执行将溶血磷脂跨脂质双层转运和翻转这一能量不利任务的分子细节仍不清楚。在这里，我们报告了五种斑马鱼 Mfsd2a（drMfsd2a）的单颗粒冷冻电镜结构：在配体自由状态下处于内向开放构象，并显示出四种不同位置的类似脂类的密度，建模为 ALA-LPC。这些 Mfsd2a 快照详细描述了脂质-LPC 从外膜小叶向内膜小叶翻转的机制，并在细胞质侧释放以进行膜整合。这些结果还映射了破坏脂质-LPC 转运并与疾病相关的 Mfsd2a 突变体。
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