Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A.
Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A.
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DOI：
10.1038/s41467-023-39088-y
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发表时间：
2023-06-09
影响因子：
16.6
通讯作者：
Khelashvili, George
中科院分区：
文献类型：
--
作者：
Bergman, Shana;Cater, Rosemary J.;Plante, Ambrose;Mancia, Filippo;Khelashvili, George
包含2 A的主要促进剂超家族结构域(MFSD2A)是一种在血-脑和血-视网膜屏障上高度丰富的转运蛋白，在那里它分别以溶质脂的形式介导Na+依赖的ω−-3脂肪酸的摄取进入大脑和眼睛。尽管最近的结构洞察，仍然不清楚这个过程是如何启动的，并由Na+驱动。在这里，我们进行了分子动力学模拟，证明底物通过跨膜螺旋5/8和2/11之间的侧向开口从膜的外叶进入MFSD2A。底物头部首先进入并与保守的谷氨酸进行Na+ 桥联作用，而尾部被疏水残基包围。这种结合模式与“陷阱和翻转”机制相一致，并触发向闭塞构象的转变。此外，使用机器学习分析，我们确定了实现这些转换的关键元素。这些结果促进了我们对MFSD2A运输周期的分子理解。MFSD2A介导的溶质脂转运到大脑的分子机制一直难以捉摸。在这里，利用分子动力学，作者揭示了MFSD2A中底物诱导的构象变化是如何使运输周期的初始阶段成为可能的。
Major Facilitator Superfamily Domain containing 2 A (MFSD2A) is a transporter that is highly enriched at the blood-brain and blood-retinal barriers, where it mediates Na+-dependent uptake of ω−3 fatty acids in the form of lysolipids into the brain and eyes, respectively. Despite recent structural insights, it remains unclear how this process is initiated, and driven by Na+. Here, we perform Molecular Dynamics simulations which demonstrate that substrates enter outward facing MFSD2A from the outer leaflet of the membrane via lateral openings between transmembrane helices 5/8 and 2/11. The substrate headgroup enters first and engages in Na+ -bridged interactions with a conserved glutamic acid, while the tail is surrounded by hydrophobic residues. This binding mode is consistent with a “trap-and-flip” mechanism and triggers transition to an occluded conformation. Furthermore, using machine learning analysis, we identify key elements that enable these transitions. These results advance our molecular understanding of the MFSD2A transport cycle. Molecular mechanisms of MFSD2A-mediated lysolipid transport into the brain has been elusive. Here, using molecular dynamics, the authors uncover how initial stages of transport cycle are enabled by substrate-induced conformational changes in MFSD2A.
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DOI：
10.1073/pnas.2215290120
发表时间：
2023-03-07
影响因子：
11.1
作者：
Chua, Geok-Lin;Tan, Bryan C.;Loke, Randy Y. J.;He, Menglan;Chin, Cheen-Fei;Wong, Bernice H.;Kuk, Alvin C. Y.;Ding, Mei;Wenk, Markus R.;Guan, Lan;Torta, Federico;Silver, David L.
通讯作者：
Silver, David L.
影响因子：
16.6
作者：
Lambert E;Mehdipour AR;Schmidt A;Hummer G;Perez C
通讯作者：
Perez C
影响因子：
2.2
作者：
Harel, Tamar;Quek, Debra Q. Y.;Edvardson, Shimon
通讯作者：
Edvardson, Shimon
影响因子：
3
作者：
Khelashvili, George;Cheng, Xiaolu;Weinstein, Harel
通讯作者：
Weinstein, Harel
影响因子：
62.1
作者：
Drew D;North RA;Nagarathinam K;Tanabe M
通讯作者：
Tanabe M