小柯机器人

omega-3脂肪酸跨血脑屏障转运的结构基础获解析
2021-06-20 15:54

美国哥伦比亚大学Filippo Mancia等研究人员合作揭示omega-3脂肪酸跨血脑屏障转运的结构基础。相关论文于2021年6月16日在线发表于国际学术期刊《自然》。

研究人员展示了使用单粒子冷冻电镜确定的MFSD2A(major facilitator superfamily domain containing 2A)结构,它显示了十二个被分成两个伪对称域的跨膜螺旋。转运蛋白呈内向构象,具有一个大的两亲性腔,其中包含Na+结合位点和结合的溶血脂底物,研究人员使用天然质谱法证实了这一点。

结合功能分析和分子动力学模拟,该结构揭示了MFSD2A如何与底物相互作用的细节,以及Na+依赖性构象变化如何允许这些底物通过侧门释放到膜中。这项工作提供了对这种非典型超家族转运蛋白介导溶血脂摄取到大脑的分子机制见解,并有可能有助于神经治疗剂的递送。

据介绍,二十二碳六烯酸是一种omega-3脂肪酸,对神经发育和功能至关重要,主要从膳食来源提供给大脑和眼睛。这种营养物质以溶血磷脂酰胆碱的形式通过MFSD2A以Na+依赖性方式运输穿过血脑屏障和血视网膜屏障 。

附:英文原文

Title: Structural basis of omega-3 fatty acid transport across the blood–brain barrier

Author: Rosemary J. Cater, Geok Lin Chua, Satchal K. Erramilli, James E. Keener, Brendon C. Choy, Piotr Tokarz, Cheen Fei Chin, Debra Q. Y. Quek, Brian Kloss, Joseph G. Pepe, Giacomo Parisi, Bernice H. Wong, Oliver B. Clarke, Michael T. Marty, Anthony A. Kossiakoff, George Khelashvili, David L. Silver, Filippo Mancia

Issue&Volume: 2021-06-16

Abstract: Docosahexaenoic acid is an omega-3 fatty acid that is essential for neurological development and function, and it is supplied to the brain and eyes predominantly from dietary sources1,2,3,4,5,6. This nutrient is transported across the blood–brain and blood–retina barriers in the form of lysophosphatidylcholine by major facilitator superfamily domain containing 2A (MFSD2A) in a Na+-dependent manner7,8. Here we present the structure of MFSD2A determined using single-particle cryo-electron microscopy, which reveals twelve transmembrane helices that are separated into two pseudosymmetric domains. The transporter is in an inward-facing conformation and features a large amphipathic cavity that contains the Na+-binding site and a bound lysolipid substrate, which we confirmed using native mass spectrometry. Together with our functional analyses and molecular dynamics simulations, this structure reveals details of how MFSD2A interacts with substrates and how Na+-dependent conformational changes allow for the release of these substrates into the membrane through a lateral gate. Our work provides insights into the molecular mechanism by which this atypical major facility superfamily transporter mediates the uptake of lysolipids into the brain, and has the potential to aid in the delivery of neurotherapeutic agents.

DOI: 10.1038/s41586-021-03650-9

Source: https://www.nature.com/articles/s41586-021-03650-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

分享到:

0