Mechanisms & Energetics of Transmembrane-induced Signaling of Cytokine Receptors

机制

基本信息

批准号：
7862768
负责人：
Wonpil Im
金额：
$ 29.45万
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）结构域如何跨细胞膜传递信号长期以来一直是生物学界密切关注的主题。细胞因子受体超家族的激活机制最近发生了范式转变。细胞因子激素与细胞外结构域结合的作用现在被认为是预二聚化TM结构域构象变化的“诱导物”，从而触发随后的细胞内反应。这与其作为“组织者”的传统角色截然不同，后者的唯一功能是启动受体TM二聚体的形成。我们的长期目标是描述配体结合后从非活性到活性转变期间各种单程TM受体的TM诱导信号传导的机制和伴随的能量学。我们的假设是，非活性断态构象比活性开态构象稳定得多，配体结合的主要作用是破坏锁定断态的预二聚化（能量稳定）TM-TM 接触。 -态结构，引导（能量不稳定的）通态结构。在本提案中，我们将使用人生长激素受体（hGHR）和人催乳素受体（hPRLR）作为同二聚体TM诱导激活的原型模型系统。该提案的目的是确定 hGHR 和 hPRLR TM 二聚体的界面残基，并通过多功能计算和实验方法的创新、多学科组合来阐明激活过程中的构象和能量变化。该项目的成功完成将对该领域产生重大影响，不仅阐明了TM信号机制和能量学，而且提供了可用于表征其他细胞因子受体和细胞因子的生物激活过程的计算和实验方法。还有大量其他单程 TM 受体，它们对生物学乃至人类健康都至关重要。公共健康相关性：膜蛋白的跨膜结构域如何跨细胞膜传递信号长期以来一直是生物学界关注和挑战的主题。该项目不仅旨在阐明跨膜信号传导机制和能量学，而且提供可用于表征其他细胞因子受体的生物激活过程和大量其他单程跨膜受体的计算和实验方法，这些受体都具有对生物学乃至人类健康至关重要。