Structural and Functional Roles of the Membrane-Related Components of Single-Pass Membrane Proteins

单程膜蛋白膜相关成分的结构和功能作用

• 批准号: 10380877
• 负责人: JAMES Jeiwen CHOU
• 金额: $ 44.2万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380877
• 关键词: Agonist; Antigens; Biochemistry; Biological; Biological Process; Biology; Cell surface; Chimeric Proteins; Coronavirus; Cytokine Receptors; Development; Exhibits; Family; Goals; HIV vaccine; HIV-1; Immunologic Receptors; Immunotherapy; Integral Membrane Protein; Interleukin Receptor; Laboratories; Ligand Binding; Link; Mediating; Membrane; Membrane Fusion; Membrane Proteins; Motivation; Receptor Signaling; Research; Role; SIV; Signal Pathway; Signal Transduction; Structure; Technology; Testing; Translating; Transmembrane Domain; Tumor Necrosis Factor Receptor; Viral; Viral Fusion Proteins; antagonist; coronavirus vaccine; design; extracellular; insight; member; receptor; vaccine development; Agonist; Antigens; Biochemistry; Biological; Biological Process; Biology; Cell surface; Chimeric Proteins; Coronavirus; Cytokine Receptors; Development; Exhibits; Family; Goals; HIV vaccine; HIV-1; Immunologic Receptors; Immunotherapy; Integral Membrane Protein; Interleukin Receptor; Laboratories; Ligand Binding; Link; Mediating; Membrane; Membrane Fusion; Membrane Proteins; Motivation; Receptor Signaling; Research; Role; SIV; Signal Pathway; Signal Transduction; Structure; Technology; Testing; Translating; Transmembrane Domain; Tumor Necrosis Factor Receptor; Viral; Viral Fusion Proteins; antagonist; coronavirus vaccine; design; extracellular; insight; member; receptor; vaccine development

PROJECT SUMMARY My laboratory investigates the structural and functional roles of the transmembrane (TM) and membrane- proximal (MP) regions of immune receptors and viral fusion proteins. The single-pass transmembrane (TM) proteins account for the vast majority of signaling receptors on the cell surface, and due to the lack of structural information, the TM/MP regions are often the missing link in our understanding of how extracellular ligand binding is translated to the activation of intracellular signaling pathways. TM and MP regions of single-pass membrane proteins are extremely difficult to visualize. We have developed an effective NMR/biochemistry technology platform for visualizing these regions and found that they can have surprisingly important biological function other than membrane anchoring. We find that a few receptors in the tumor necrosis factor receptor superfamily (TNFRSF) exhibit a previously unknown phenomenon that their transmembrane domains (TMDs) alone can oligomerize in membrane and drive receptor clustering and activation. In another finding, the TM region of the HIV-1 envelope spike form defined trimeric structure that can strongly influence the antigenicity of the ectodomain of the spike currently being used for vaccine development. The above few examples already suggest the enormous potential of uncovering the membrane regions of type I/II membrane proteins in discovering new biological mechanisms, which is the motivation for the proposed research. In the next five years, we will continue to explore the structure and function of TM regions with three specific goals. (1) We will further examine the mechanism of TMD-mediated receptor clustering and activation for other members of the TNFRSF and test the generality of this new concept in receptor biology. (2) We will explore the function of TMD oligomerization in the signaling mechanism of the  chain cytokine receptors, for which the membrane regions are completely unknown. (3) We will continue to examine the TM and MP regions of other viral fusion proteins such as that of SIV and coronavirus, for understanding how the membrane-interacting components of the fusion proteins stabilize the prefusion state of the envelope spikes and for revealing unique structural features that may be used for testing mechanistic hypotheses of viral membrane fusion.

项目摘要 我的实验室研究了跨膜（TM）和膜的结构和功能作用 免疫受体和病毒融合蛋白的近端（MP）区域。单通跨膜（TM） 蛋白质占细胞表面上绝大多数信号接收器的解释，并且由于缺乏结构 信息，TM/MP区域通常是我们对细胞外配体结合的理解中缺少的联系 被翻译成细胞内信号通路的激活。单通膜的TM和MP区域 蛋白质极难可视化。我们已经开发了有效的NMR/生物化学技术 可视化这些区域的平台，发现它们可以具有令人惊讶的重要生物学功能 比膜锚定。我们发现肿瘤坏死因子受体超家族中的一些受体 （TNFRSF）暴露了以前未知的现象，即它们的跨膜结构域（TMD）可以 在膜上寡聚，并驱动受体聚类和激活。在另一个发现中， HIV-1包膜尖峰形式定义了三聚体结构，可以强烈影响 目前用于疫苗开发的尖峰的外体域。以上几个例子已经暗示 发现新的I/II膜蛋白的膜区域的巨大潜力 生物学机制，这是拟议研究的动机。在接下来的五年中，我们将继续 探索具有三个特定目标的TM区域的结构和功能。 （1）我们将进一步研究 TMD介导的受体聚类和激活的机制，用于TNFRSF的其他成员并测试 这种新概念在受体生物学中的普遍性。 （2）我们将探讨TMD寡聚的功能 链细胞因子受体的信号传导机制，膜区域完全未知。 （3）我们将继续研究其他病毒融合蛋白的TM和MP区域，例如SIV和SIV和MP 冠状病毒，以了解融合蛋白的膜相互作用成分如何稳定 信封尖峰的预选状态，并揭示可用于测试的独特结构特征 病毒膜融合的机械假设。