小柯机器人

美国斯坦福大学医学院Liang Feng研究团队揭示血脑屏障脂质转运蛋白MFSD2A的结构与机制。这一成果由相关论文发表在2021年8月4日出版的《自然》杂志上。

他们报告了小鼠 MFSD2A 的冷冻电镜结构。他们的结构定义了这一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——连同他们的功能研究和分子动力学模拟——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，并有助于使小头畸形症的基础 MFSD2A 突变合理化。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。

据悉，MFSD2A 是一种钠依赖性溶血磷脂酰胆碱同向转运蛋白，负责将二十二碳六烯酸摄取到大脑，这对大脑的发育和性能至关重要。影响 MFSD2A 的突变会导致小头畸形综合征。 MFSD2A 转运脂质的能力也是其作为胞吞作用抑制剂调节血脑屏障功能的关键机制。因此，MFSD2A 代表了一个有吸引力的目标，用于调节血脑屏障的通透性以进行药物递送。

附：英文原文

Title: Structure and mechanism of blood–brain-barrier lipid transporter MFSD2A

Author: Wood, Chase A. P., Zhang, Jinru, Aydin, Deniz, Xu, Yan, Andreone, Benjamin J., Langen, Urs H., Dror, Ron O., Gu, Chenghua, Feng, Liang

Issue&Volume: 2021-08-04

Abstract: MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain1,2, which is crucial for the development and performance of the brain3. Mutations that affect MFSD2A cause microcephaly syndromes4,5. 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 barrier6,7. 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.

DOI: 10.1038/s41586-021-03782-y

Source: https://www.nature.com/articles/s41586-021-03782-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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