Mechanisms & Energetics of Transmembrane-induced Signaling of Cytokine Receptors

机制

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8098698
• 关键词: Address; Area; Binding; Biological; Biological Models; Biology; Cell membrane; Cell surface; Cysteine; Cytokine Receptors; Data; Disulfides; Electron Spin Resonance Spectroscopy; Event; Extracellular Domain; Feedback; Free Energy; Health; Hormones; Human; Ligand Binding; Ligands; Link; Measures; Membrane; Membrane Proteins; Methods; Modeling; Molecular; Molecular Conformation; Positioning Attribute; Process; Prolactin Receptor; Receptor Activation; Role; Sequence Homology; Side; Signal Transduction; Simulate; Site; Spin Labels; Structure; System; Testing; Transmembrane Domain; base; cytokine; dimer; disulfide bond; extracellular; foot; human GHR protein; innovation; interest; interfacial; membrane model; molecular dynamics; multidisciplinary; public health relevance; receptor; research study; response; restraint; simulation

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中非常感兴趣的主题。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”，其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二聚体的形成。我们的长期目标是描绘的机制和伴随的能量TM诱导的信号传导的各种单程TM受体在非活性到活性的过渡后，配体结合。我们的假设是，非活性关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关态结构的预二聚（能量稳定）TM-TM接触，以指导（能量不稳定）开态结构。在这个提议中，我们将使用人生长激素受体（hGHR）和人催乳素受体（hPRLR）作为同型二聚体TM诱导激活的原型模型系统。本提案的目的是确定hGHR和hPRLR TM二聚体的界面残基，并阐明在激活过程中的构象和能量变化的创新，多学科的通用计算和实验方法相结合。该项目的成功完成将对该领域产生重大影响，不仅阐明TM信号机制和能量学，而且提供可用于表征其他细胞因子受体的生物激活过程的计算和实验方法。其他单程TM受体的丰富性，这些都对生物学以及人类健康至关重要。 公共卫生相关性：膜蛋白的跨膜结构域如何跨膜传递信号一直是生物学研究的热点和挑战。该项目旨在不仅阐明跨膜信号传导机制和能量学，而且还提供可用于表征其他细胞因子受体的生物激活过程和其他单程跨膜受体的生物活性的计算和实验方法，这些都对生物学和人类健康至关重要。