MFSD2A 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 brain³. 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.

MFSD2A 是一种钠依赖性溶血磷脂酰胆碱同向转运体，负责将二十二碳六烯酸摄取到大脑中^1,2，这对大脑的发育和表现至关重要³。影响 MFSD2A 的突变会导致小头畸形综合征^4,5。MFSD2A 转运脂质的能力也是其作为转胞吞作用抑制剂调节血脑屏障功能的关键机制^6,7. 因此，MFSD2A 代表了一个有吸引力的靶标，用于调节血脑屏障的通透性以进行药物输送。在这里，我们报告了小鼠 MFSD2A 的冷冻电子显微镜结构。我们的结构定义了这种重要转运蛋白的结构，揭示了其独特的细胞外结构域并揭示了其底物结合腔。该结构与我们的功能研究和分子动力学模拟一起确定了一个保守的钠结合位点，揭示了一个潜在的脂质进入途径，并有助于合理化小头畸形综合征背后的MFSD2A突变。这些结果阐明了 MFSD2A 的关键脂质转运功能，并提供了一个框架来帮助设计用于治疗目的的特定调节剂。