Structural insights into the lysophospholipid brain uptake mechanism and its inhibition by syncytin-2
Structural insights into the lysophospholipid brain uptake mechanism and its inhibition by syncytin-2
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溶血磷脂脑摄取机制的结构见解及其受合胞素-2的抑制
DOI：
10.1038/s41594-022-00786-8
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发表时间：
2022-06-16
影响因子：
16.8
通讯作者：
Reyes, Nicolas
中科院分区：
文献类型：
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作者：
Martinez-Molledo, Maria;Nji, Emmanuel;Reyes, Nicolas
大脑发育和功能需要通过主要易化超家族转运蛋白MFSD 2A以溶血磷脂酰胆碱的形式摄取必需的ω-3脂肪酸，MFSD 2A是调节血脑屏障（BBB）通透性的潜在药物靶点。MFSD 2A也是人胎盘中内源性逆转录病毒包膜合胞素-2（SYNC 2）的受体，在胎盘中它介导细胞-细胞融合和母胎界面的形成。在这里，我们报告了冷冻电子显微镜结构的人类MFSD 2A-SYNC 2复合物，揭示了一个大的疏水腔在转运蛋白C-末端结构域闭塞长脂肪链。转运蛋白结构表明哺乳动物MFS转运蛋白中脂质底物的交替进入转运机制。SYNC 2与MFSD 2A建立了广泛的结合界面，并且SYNC 2可溶性片段充当长期寻求的MFSD 2A转运抑制剂。我们的工作揭示了对大脑和胎盘发育和功能重要的分子机制，SYNC 2介导的MFSD 2A转运抑制提出了帮助治疗性大分子穿过BBB的策略。
Brain development and function require uptake of essential omega-3 fatty acids in the form of lysophosphatidylcholine via major-facilitator superfamily transporter MFSD2A, a potential pharmaceutical target to modulate blood-brain barrier (BBB) permeability. MFSD2A is also the receptor of endogenous retroviral envelope syncytin-2 (SYNC2) in human placenta, where it mediates cell-cell fusion and formation of the maternal-fetal interface. Here, we report a cryo-electron microscopy structure of the human MFSD2A-SYNC2 complex that reveals a large hydrophobic cavity in the transporter C-terminal domain to occlude long aliphatic chains. The transporter architecture suggests an alternating-access transport mechanism for lipid substrates in mammalian MFS transporters. SYNC2 establishes an extensive binding interface with MFSD2A, and a SYNC2-soluble fragment acts as a long-sought-after inhibitor of MFSD2A transport. Our work uncovers molecular mechanisms important to brain and placenta development and function, and SYNC2-mediated inhibition of MFSD2A transport suggests strategies to aid delivery of therapeutic macromolecules across the BBB.