Altered plasma membrane abundance of the sulfatide-binding protein NF155 links glycosphingolipid imbalances to demyelination
Altered plasma membrane abundance of the sulfatide-binding protein NF155 links glycosphingolipid imbalances to demyelination
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硫苷脂结合蛋白 NF155 质膜丰度的改变将鞘糖脂失衡与脱髓鞘联系起来
DOI：
10.1101/2022.09.15.508082
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
McKie S
中科院分区：
文献类型：
--
作者：
McKie S
髓磷脂是一种多层膜，紧密包裹神经元轴突，使有效，高速的信号传播。轴突和髓鞘形成紧密接触，由特定的质膜蛋白和脂质介导，这些接触的破坏导致破坏性的脱髓鞘疾病。使用两个细胞为基础的模型脱髓鞘鞘脂，我们表明，改变脂质代谢的变化丰富的特定质膜蛋白。这些改变的膜蛋白在细胞粘附和信号传导中具有已知的作用，其中一些涉及神经系统疾病。神经成束蛋白（NFASC）是维持髓鞘-轴突接触的关键蛋白质，其细胞表面丰度在鞘脂代谢中断后发生变化。这提供了改变的脂质丰度和髓磷脂稳定性之间的直接分子联系。我们表明，NFASC亚型NF 155，但不是NF 186，直接和特异性的相互作用与鞘脂硫脂通过多个结合位点，这种相互作用需要全长细胞外结构域NF 155。我们证明，NF 155采用S形构象，并优先结合含硫酸脂膜切口，在紧张的轴突髓鞘空间的蛋白质排列的重要影响。我们的工作将鞘糖脂失衡与膜蛋白丰度的干扰联系起来，并证明了这可能是由直接的蛋白质-脂质相互作用驱动的，为理解半乳糖鞘脂病的发病机制提供了一个机制框架。
Myelin is a multilayered membrane that tightly wraps neuronal axons, enabling efficient, high-speed signal propagation. The axon and myelin sheath form tight contacts, mediated by specific plasma membrane proteins and lipids, and disruption of these contacts causes devastating demyelinating diseases. Using two cell-based models of demyelinating sphingolipidoses, we demonstrate that altered lipid metabolism changes the abundance of specific plasma membrane proteins. These altered membrane proteins have known roles in cell adhesion and signaling, with several implicated in neurological diseases. The cell surface abundance of the adhesion molecule neurofascin (NFASC), a protein critical for the maintenance of myelin-axon contacts, changes following disruption to sphingolipid metabolism. This provides a direct molecular link between altered lipid abundance and myelin stability. We show that the NFASC isoform NF155, but not NF186, interacts directly and specifically with the sphingolipid sulfatide via multiple binding sites and that this interaction requires the full-length extracellular domain of NF155. We demonstrate that NF155 adopts an S-shaped conformation and preferentially binds sulfatide-containing membranes incis, with important implications for protein arrangement in the tight axon-myelin space. Our work links glycosphingolipid imbalances to disturbance of membrane protein abundance and demonstrates how this may be driven by direct protein–lipid interactions, providing a mechanistic framework to understand the pathogenesis of galactosphingolipidoses.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1073/pnas.93.23.13280
发表时间：
1996-11-12
影响因子：
11.1
作者：
Bosio, A;Binczek, E;Stoffel, W
通讯作者：
Stoffel, W
BioImage Archive - 构建生命科学显微镜数据之家
DOI：
10.1101/2021.12.17.473169
发表时间：
2021
期刊：
--
影响因子：
--
作者：
Hartley M
通讯作者：
Hartley M
影响因子：
5.3
作者：
McGonigal, Rhona;Barrie, Jennifer A.;Willison, Hugh J.
通讯作者：
Willison, Hugh J.
DOI：
10.1073/pnas.1220104110
发表时间：
2013-02-19
影响因子：
11.1
作者：
Bakhti, Mostafa;Snaidero, Nicolas;Simons, Mikael
通讯作者：
Simons, Mikael