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.

项目概要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）区域。蛋白质占细胞表面信号受体的绝大多数，并且由于缺乏结构信息，TM/MP 区域通常是我们理解细胞外配体如何结合的缺失环节被翻译为单通膜的细胞内信号传导通路的激活。蛋白质的可视化极其困难，我们开发了一种有效的 NMR/生物化学技术。可视化这些区域的平台，发现它们可以具有其他令人惊讶的重要生物功能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）单独可以在另一个发现中，TM 区域在膜中寡聚并驱动受体聚集和激活。 HIV-1 包膜刺突形成明确的三聚体结构，可强烈影响 HIV-1 包膜的抗原性目前用于疫苗开发的刺突的胞外域。该区域在发现新的 I/II 型膜蛋白膜方面具有巨大的潜力生物学机制，这是未来五年我们将继续进行这项研究的动机。（一）我们将进一步研究 TNFRSF 其他成员的 TMD 介导的受体聚集和激活机制并测试 (2)我们将探讨TMD寡聚化在受体生物学中的功能。 γ链细胞因子受体的信号传导机制，其膜区域完全未知。 (3)我们将继续检查其他病毒融合蛋白的TM和MP区域，例如SIV和冠状病毒，用于了解融合稳定蛋白的膜相互作用成分如何包络尖峰的预融合状态，并揭示可用于测试的独特结构特征病毒膜融合的机制假设。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A trimeric hydrophobic zipper mediates the intramembrane assembly of SARS-CoV-2 spike.

三聚体疏水拉链介导 SARS-CoV-2 刺突的膜内组装。

DOI：
发表时间：
2021-04-10
期刊：
影响因子：
0
作者：
Fu, Qingshan;Chou, James J
通讯作者：
Chou, James J

Autoinhibitory structure of preligand association state implicates a new strategy to attain effective DR5 receptor activation.

前配体缔合状态的自抑制结构暗示了一种实现有效 DR5 受体激活的新策略。

DOI：
发表时间：
2023-02
期刊：
影响因子：
44.1
作者：
Du, Gang;Zhao, Linlin;Zheng, Yumei;Belfetmi, Anissa;Cai, Tiantian;Xu, Boying;Heyninck, Karen;Van Den Heede, Kim;Buyse, Marie;Fontana, Pietro;Bowman, Michael;Lin, Lih;Wu, Hao;Chou, James Jeiwen
通讯作者：
Chou, James Jeiwen

A Trimeric Hydrophobic Zipper Mediates the Intramembrane Assembly of SARS-CoV-2 Spike.

三聚体疏水拉链介导 SARS-CoV-2 刺突的膜内组装。