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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结我的实验室研究跨膜(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。单程跨膜(TM) 蛋白质占细胞表面信号受体的绝大多数，由于缺乏结构信息，TM/MP区域往往是我们理解细胞外配体结合方式的缺失环节转化为细胞内信号通路的激活。单程膜的TM区和MP区蛋白质是极难想象的。我们已经开发出一种有效的核磁共振/生化技术可视化这些区域的平台，并发现它们可以具有令人惊讶的重要生物功能而不是膜锚定。我们发现肿瘤坏死因子受体超家族中的一些受体 (TNFRSF)表现出一种以前未知的现象，即它们的跨膜结构域(TMD)本身可以在膜上寡聚，并驱动受体聚集和激活。在另一项发现中，该物种的TM区域 HIV-1包膜尖峰形式定义的三聚体结构可以强烈影响HIV-1的抗原性目前用于疫苗开发的尖峰的胞外区域。上面的几个例子已经表明揭示I型/II型膜蛋白膜区在发现新的生物学机制，这是拟议研究的动机。在未来五年，我们将继续以三个具体目标探索TM区域的结构和功能。(1)我们会进一步研究 TMD介导的TNFRSF其他成员的受体聚集和激活机制，并测试受体生物学中这一新概念的概括性。(2)我们将探讨TMD齐聚在基因工程中的作用。 链细胞因子受体的信号机制，其膜区域完全未知。 (3)我们会继续研究其他病毒融合蛋白的TM和MP区，例如SIV和冠状病毒，以了解融合蛋白的膜相互作用成分如何稳定包膜尖峰的预熔状态并揭示可用于测试的独特结构特征病毒膜融合的机制假说。