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Functional Motions of Modular Signaling Proteins

模块化信号蛋白的功能运动

基本信息

批准号：
8242043
负责人：
JEFFREY W PENG
金额：
$ 24.85万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242043
关键词：
Active Sites Adopted Affect Affinity Alzheimer&apos s Disease Binding Biochemical Biological Biological Models Biology Catalysis Catalytic Domain Cell Cycle Cell Cycle Proteins Cell Survival Cells Chemicals Communication Complex Disease Docking Goals Health Human Human Biology Individual Investigation Isomerase Length Life Ligands Link Malignant Neoplasms Mediating Mitotic Modeling Molecular Motion Nuclear Magnetic Resonance Orthologous Gene Pathogenesis Phosphoric Monoester Hydrolases Phosphotransferases Principal Investigator Process Property Protein Dynamics Proteins Publishing Research Role Side Signal Transduction Signaling Protein Specificity Structure Testing Work Yeasts base cell growth computer studies computerized data processing design flexibility inhibitor/antagonist insight new therapeutic target paralogous gene preference programs protein protein interaction stem therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Understanding the pathogenesis of cell cycle diseases (e.g., cancer) is complex due to the multiplicity of protein-protein interactions that must be considered. The view of protein-protein interactions as highly inter-connected networks embraces this complexity at the outset, and holds out the promise for the discovery of new therapeutic targets and strategies. To realize this promise, we must understand how key network proteins - modular signaling proteins - drive cellular signal transduction. Mounting evidence shows that these proteins have significant conformational dynamics that change upon target binding. This suggests a functional link between network signaling and protein motion. Yet, most analyses of protein interaction networks implicitly assume static structures. Hence, defining the influence of conformational dynamics on signaling within protein-protein interaction networks remains an outstanding challenge in biology. The goal of our proposed research is to deepen our understanding of how the functional motions of modular signaling proteins affects normal versus pathogenic network signaling, and eventually suggest new strategies for the design of ligands targeting dynamic modular proteins. Toward this goal, we explore two hypotheses developed from our recent work: (1) modular signaling proteins vary the sequences of their recognition loops to enhance binding preference; this has implications for interaction diversity and signal routing within the network; (2) modular signaling proteins use inter-domain interactions to stimulate changes in dynamics that allosterically modulate catalytic activity; this has implications for the mechanisms by which individual proteins process chemical signals. To investigate these hypotheses, we propose NMR investigations of dynamics-activity relationships in a model protein, human Pin1. Pin1 is a mitotic regulator consisting of a docking module (WW domain) flexibly linked to a catalytic module (isomerase domain), and is a current cancer target. Its robust biochemical properties make it an excellent model system for exploring fundamental properties of modular proteins. Investigations will use full-length Pin1, its isolated domains, and known Pin1 substrates/inhibitors. PUBLIC HEALTH RELEVANCE This proposal describes studies of a model system to understand how intrinsic protein dynamics enable biological networks to maintain cell survival and growth. The proposed research will provide new insights into the molecular origins of disease.

描述（由申请人提供）：了解细胞周期疾病的发病机制（例如，癌症）是复杂的，因为必须考虑蛋白质-蛋白质相互作用的多样性。蛋白质-蛋白质相互作用作为高度相互连接的网络的观点从一开始就包含了这种复杂性，并为发现新的治疗靶点和策略带来了希望。为了实现这一承诺，我们必须了解关键网络蛋白-模块信号蛋白-如何驱动细胞信号转导。越来越多的证据表明，这些蛋白质具有显着的构象动力学的目标结合后发生变化。这表明网络信号和蛋白质运动之间存在功能联系。然而，大多数蛋白质相互作用网络的分析隐含地假设静态结构。因此，确定构象动力学对蛋白质-蛋白质相互作用网络中信号传导的影响仍然是生物学中的一个突出挑战。我们提出的研究的目标是加深我们对模块化信号蛋白的功能运动如何影响正常与致病网络信号的理解，并最终提出针对动态模块化蛋白的配体设计的新策略。为了实现这一目标，我们探讨了从我们最近的工作中发展起来的两个假设：（1）模块化信号蛋白改变其识别环的序列以增强结合偏好，这对网络内的相互作用多样性和信号路由有影响;（2）模块化信号蛋白利用结构域间的相互作用来刺激动力学的变化，从而变构地调节催化活性;这暗示了单个蛋白质处理化学信号的机制。为了研究这些假设，我们提出了一个模型蛋白质，人类Pin 1的动态活性关系的NMR研究。Pin 1是一种有丝分裂调节因子，由一个对接模块（WW结构域）灵活连接到一个催化模块（异构酶结构域），是目前的癌症靶点。其强大的生化特性使其成为探索模块蛋白质基本特性的优秀模型系统。研究将使用全长Pin 1、其分离的结构域和已知的Pin 1底物/抑制剂。本提案描述了一个模型系统的研究，以了解内在蛋白质动力学如何使生物网络维持细胞存活和生长。这项拟议中的研究将为疾病的分子起源提供新的见解。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modeling conformational ensembles of slow functional motions in Pin1-WW.

DOI：
10.1371/journal.pcbi.1001015
发表时间：
2010-12-02
期刊：
PLoS computational biology
影响因子：
4.3
作者：
Morcos F;Chatterjee S;McClendon CL;Brenner PR;López-Rendón R;Zintsmaster J;Ercsey-Ravasz M;Sweet CR;Jacobson MP;Peng JW;Izaguirre JA
通讯作者：
Izaguirre JA

Investigating Dynamic Interdomain Allostery in Pin1.