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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改变的质膜丰度的硫酸脂结合蛋白NF 155链接鞘糖脂失衡脱髓鞘。
DOI：
10.1073/pnas.2218823120
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发表时间：
2023-04-04
影响因子：
11.1
通讯作者：
Deane, Janet E.
中科院分区：
文献类型：
--
作者：
McKie, Shannon J.;Nicholson, Alex S.;Smith, Emily;Fawke, Stuart;Caroe, Eve R.;Williamson, James C.;Butt, Benjamin G.;Kolarova, Denisa;Peterka, Ondrej;Holcapek, Michal;Lehner, Paul J.;Graham, Stephen C.;Deane, Janet E.
鞘糖脂是一类重要的脂类，富集于质膜外小叶。改变鞘糖脂代谢的疾病会导致毁灭性的神经退行性疾病和脱髓鞘疾病。我们发现鞘糖脂代谢酶GALC或UGT8的缺失会导致特定质膜蛋白丰度的显著变化，其中一些与退行性脑疾病有关。我们通过表征膜蛋白神经束蛋白与鞘糖脂硫脂的特定相互作用来扩展这一发现。神经束蛋白的胞外结构域与多个硫脂分子结合，使其能够沿着自身的膜平面结合，这解释了其对脂质组成改变的敏感性。这项工作将鞘糖脂代谢疾病与疾病表型相关的质膜变化联系起来。髓磷脂是一种多层膜，紧密包裹神经元轴突，使信号高效、高速传播。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毁灭性的脱髓鞘疾病。使用两种基于细胞的脱髓鞘脂质病模型，我们证明了脂质代谢的改变改变了特定质膜蛋白的丰度。这些改变的膜蛋白已知在细胞粘附和信号传导中起作用，其中一些与神经系统疾病有关。黏附分子神经束蛋白（NFASC）是维持髓鞘-轴突接触的关键蛋白，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。我们发现NFASC异构体NF155，而不是NF186，通过多个结合位点直接特异性地与鞘脂硫脂相互作用，并且这种相互作用需要NF155的全长胞外结构域。我们证明NF155采用s形构象，并优先顺式结合含硫脂的膜，这对紧密的轴突-髓鞘空间中的蛋白质排列具有重要意义。我们的工作将鞘糖脂失衡与膜蛋白丰度的紊乱联系起来，并证明了这可能是由直接的蛋白-脂相互作用驱动的，为理解半乳糖鞘脂病的发病机制提供了一个机制框架。
Glycosphingolipids are an important class of lipids enriched in the outer leaflet of the plasma membrane. Disorders that alter glycosphingolipid metabolism cause devastating neurodegenerative and demyelinating diseases. We show that deletion of the glycosphingolipid metabolizing enzymes GALC or UGT8 cause significant changes to the abundance of specific plasma membrane proteins, several of which are implicated in degenerative brain disease. We extend this discovery by characterizing the specific interaction of the membrane protein neurofascin with the glycosphingolipid sulfatide. The extracellular domain of Neurofascin binds multiple sulfatide molecules, allowing it to bind flat along its own membrane, explaining its sensitivity to altered lipid composition. This work links diseases of glycosphingolipid metabolism to changes at the plasma membrane relevant to disease phenotypes. 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 in cis, 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：
3.8
作者：
Fuller, Maria;Rozaklis, Tina;Meikle, Peter J.
通讯作者：
Meikle, Peter J.
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
影响因子：
9.2
作者：
Charles, P;Tait, S;Lubetzki, C
通讯作者：
Lubetzki, C
影响因子：
14.9
作者：
Brinkman EK;Chen T;Amendola M;van Steensel B
通讯作者：
van Steensel B
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