NMR Model of the Entire Membrane-Interacting Region of the HIV-1 Fusion Protein and Its Perturbation of Membrane Morphology.
NMR Model of the Entire Membrane-Interacting Region of the HIV-1 Fusion Protein and Its Perturbation of Membrane Morphology.
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DOI：
10.1021/jacs.1c01762
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发表时间：
2021-04
影响因子：
15
通讯作者：
A. Piai;Q. Fu;Amanda Sharp;B. Bighi;A. M. Brown;J. Chou
中科院分区：
文献类型：
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作者：
A. Piai;Q. Fu;Amanda Sharp;B. Bighi;A. M. Brown;J. Chou
HIV-1包膜糖蛋白（ENV）是一种跨膜蛋白，可介导膜融合和病毒。 ENV的膜相互作用区域，包括膜 - 透明体外部区域（MPER），跨膜结构域（TMD）和细胞质尾部（CT），不仅对融合和Envistion是必不可少的，而且还可以强烈影响Env的抗原性。先前的研究逐渐揭示了CT的MPER，TMD和KS-LLP2区域的结构。在这里，我们使用包含TMD和CT的蛋白质片段确定了全长CT的NMR结构，该蛋白质片段模仿了脂质双层，并通过整合了新的NMR数据以及以前在其他GP41片段上获得的蛋白质，我们得出了整个Membrane Inctacting Eust Inventing Andactrane Incranting区域的模型。该结构表明，CT在TMD三聚体周围形成大型三聚底板，并且通过居住在脂质双层的头组区域，底板会导致双层细胞脂质中严重排除脂质。全原子分子动力学模拟表明，MPER-TMD-CT的整体结构可以在病毒膜上保持稳定，并且KS-LLP2区域的一致运动可以补偿脂质排除，以维持结构和膜完整性。我们的结构和仿真结果为未来的研究提供了一个框架，以操纵膜结构，以调节ENV在疫苗开发中的抗原性以及用于研究膜融合并与基质蛋白相互作用的诱变研究。
HIV-1 envelope glycoprotein (Env) is a transmembrane protein that mediates membrane fusion and viral entry. The membrane-interacting regions of the Env, including the membrane-proximal external region (MPER), the transmembrane domain (TMD), and the cytoplasmic tail (CT), not only are essential for fusion and Env incorporation but also can strongly influence the antigenicity of the Env. Previous studies have incrementally revealed the structures of the MPER, the TMD, and the KS-LLP2 regions of the CT. Here, we determined the NMR structure of the full-length CT using a protein fragment comprising the TMD and the CT in bicelles that mimic a lipid bilayer, and by integrating the new NMR data and those acquired previously on other gp41 fragments, we derived a model of the entire membrane-interacting region of the Env. The structure shows that the CT forms a large trimeric baseplate around the TMD trimer, and by residing in the headgroup region of the lipid bilayer, the baseplate causes severe exclusion of lipid in the cytoleaflet of the bilayer. All-atom molecular dynamics simulations showed that the overall structure of the MPER-TMD-CT can be stable in a viral membrane and that a concerted movement of the KS-LLP2 region compensates for the lipid exclusion in order to maintain both structure and membrane integrity. Our structural and simulation results provide a framework for future research to manipulate the membrane structure to modulate the antigenicity of the Env for vaccine development and for mutagenesis studies for investigating membrane fusion and Env interaction with the matrix proteins.