Mechanisms & Energetics of Transmembrane-induced Signaling of Cytokine Receptors

机制

基本信息

批准号：
8098698
负责人：
Wonpil Im
金额：
$ 27.99万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): How transmembrane (TM) domains of membrane proteins transmit the signal across the cell membrane has long been a subject of keen interest in biology. There is a recent paradigm shift in the mechanism of activation for the cytokine receptor superfamily. The role of cytokine hormone binding to the extracellular domain is now recognized as an "inducer" of the conformational change of pre-dimerized TM domains that triggers subsequent intracellular responses. This is drastically different from its traditional role as an "organizer" whose sole function was to initiate the receptor TM dimer formation. Our long-term objective is to delineate the mechanisms and accompanying energetics of TM-induced signaling of various single-pass TM receptors during the inactive to active transition upon ligand binding. Our hypothesis is that the inactive off-state conformation is much more stable than the active on-state one, and the major role of ligand binding is to disrupt the pre-dimerized (energetically stable) TM-TM contact that locks-in the off-state structure, to direct the (energetically unstable) on-state structure. In this proposal, we will use human growth hormone receptor (hGHR) and human prolactin receptor (hPRLR) as prototypical model systems for homodimeric TM-induced activation. The objectives of this proposal are to determine the interfacial residues of hGHR and hPRLR TM dimers and to elucidate the conformational and energetic changes during the activation process by innovative, multidisciplinary combination of versatile computational and experimental approaches. The successful completion of this project will have a significant impact on the field, not only by elucidating the TM signaling mechanism and energetics, but also by providing the computational and experimental methods that can be used to characterize the biological activation process of other cytokine receptors and the plentitude of other single-pass TM receptors, which all have the critical importance to biology and thus, human health. PUBLIC HEALTH RELEVANCE: How transmembrane domains of membrane proteins transmit the signal across the cell membrane has long been a subject of interest and challenge in biology. This project seeks to not only elucidate the transmembrane signaling mechanism and energetics, but also provide the computational and experimental methods that can be used to characterize the biological activation process of other cytokine receptors and the plentitude of other single-pass transmembrane receptors, which all have the critical importance to biology and thus, human health.

描述（由申请人提供）：膜蛋白的跨膜（TM）结构域如何在整个细胞膜上传递信号一直是生物学兴趣的主题。最近，细胞因子受体超家族的激活机理发生了范式转移。现在，细胞因子激素与细胞外结构域结合的作用被认为是预测的TM结构域的构象变化的“诱导剂”，这会触发随后的细胞内反应。这与其作为“组织者”的传统作用截然不同，其唯一功能是启动受体TM二聚体形成。我们的长期目标是描述在配体结合时无效到主动过渡期间，TM诱导的各种单通TM受体信号传导的机制和伴随的能量学。我们的假设是，不活跃的外态构象比活跃的态构型要稳定得多，配体结合的主要作用是破坏锁定在状态结构中的预测（能量稳定）的TM-TM接触，以指导（能量稳定的）态结构。在此提案中，我们将使用人类生长激素受体（HGHR）和人催乳素受体（HPRLR）作为均二聚体TM诱导的激活的典型模型系统。该提案的目标是确定HGHR和HPRLR TM二聚体的界面残基，并通过创新的，多功能计算和实验方法的多学科组合在激活过程中阐明构象和能量变化。该项目的成功完成将对该领域产生重大影响，这不仅是通过阐明TM信号传导机制和能量学，而且还通过提供可用于表征其他细胞因子受体的生物激活过程的计算和实验方法，以及其他单个PASS TM受体的典范，这些过程对生物学和人类健康都具有至关重要的重要性。公共卫生相关性：膜蛋白的跨膜结构域如何在整个细胞膜上传递信号一直是生物学中感兴趣和挑战的主题。该项目不仅旨在阐明跨膜信号传导机制和能量学，还提供了计算和实验方法，可用于表征其他细胞因子受体的生物激活过程以及其他单个单个单个跨膜受体的质量，这些过程对生物学以及人类健康至关重要。