Configurational and internal dynamics of protein-protein complexes

蛋白质-蛋白质复合物的构型和内部动力学

• 批准号: 9132828
• 负责人: MATTHIAS BUCK
• 金额: $ 30.12万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132828
• 关键词: Adaptor Signaling Protein; Affect; Automobile Driving; Basic Science; Behavior; Binding; Binding Proteins; Biological; Biological Models; Cardiovascular system; Cataract; Cell membrane; Cells; Cellular Membrane; Cellular biology; Complex; Computational Biology; Computer Simulation; Development; Diagnostic; Disease; Environment; Eph Family Receptors; Family; Family member; Fluorescence; Foundations; Future; Genes; Genetic; Goals; Health; Human; INPPL1 gene; In Vitro; Individual; Investigation; Kinetics; Knowledge; Laboratories; Lead; Link; Measurement; Methods; Modeling; Modification; Molecular; Mutagenesis; Mutate; Mutation; Nature; Outcome; Phosphorylation; Post-Translational Protein Processing; Protein Dynamics; Proteins; Relaxation; Research; SAM Domain; Signal Transduction; Structure; Therapeutic; Therapeutic Agents; Tyrosine; Tyrosine Phosphorylation; Work; base; biological systems; design; human disease; in vivo; insight; member; molecular dynamics; mutant; nanosecond; nervous system development; protein complex; protein folding; protein function; protein protein interaction; receptor; receptor function; restraint; simulation; src Homology Region 2 Domain; tumor; tumorigenesis

DESCRIPTION (provided by applicant): This proposed project seeks to develop the recent paradigm that protein complexes can be multi-configurational, if not highly dynamic entities. The biophysical and functional features of such dynamic complexes need to be understood. We chose heterodimer complexes involving Eph-family SAM domains as an example. SAM domains are important as they occur in over 200 human proteins, most notably in all 14 members of human Eph receptor tyrosine kinases. These receptors function in the development of the nervous and cardiovascular systems, and recent studies have shown that the SAM domain of EphA2 is mutated in a variety of human tumors as well as cataract, both linked to EphA2 dysregulation. However, the molecular basis of the normal and abnormal function of EphA2 SAM domain is not yet understood. Using a three-pronged approach, involving biophysical, computational and cell biology methods we will characterize the multi-configurational features of EphA1-SHIP2 and EphA2-SHIP2 SAM:SAM complexes. Furthermore, we will study how tumor associated mutations affect not just protein folding, stability and aggregation, but likely affect SAM domain-protein interactions via alterations of the configurational and internal dynamics of SAM domains. We will study the effect of specific tyrosine phosphorylation in the same manner, revealing the molecular basis of these functionally important posttranslational modifications. Investigations of Eph-related SAM domain conformational dynamics and protein-protein interactions have shifted our perspective on the normal and disease function of the domain. The knowledge obtained from this basic science research will serve as a general model for other dynamic protein complexes. Furthermore, the insights obtained, may eventually lead to the design of diagnostic and therapeutic agents.

描述（由申请人提供）：该拟议的项目旨在发展最近的范式，即蛋白质复合物可以是多种配置的，即使不是高度动态的实体。需要了解这种动态复合物的生物物理和功能特征。我们选择了涉及EPH家庭SAM域的异二聚体复合物。 SAM域很重要，因为它们发生在200多种人蛋白中，最著名的是在人类EPH受体酪氨酸激酶的所有14个成员中。这些受体在神经和心血管系统的发育中起作用，最近的研究表明，Epha2的SAM结构域在各种人类肿瘤和白内障中被突变，都与Epha2失调有关。然而，尚不清楚epha2 sam域的正常和异常功能的分子基础。使用涉及生物物理，计算和细胞生物学方法的三个普通方法，我们将表征Epha1-Ship2和Epha2-Ship2 Sam：Sam Complextes的多种配置特征。此外，我们将研究肿瘤相关的突变不仅影响蛋白质折叠，稳定性和聚集，而且可能通过改变而影响SAM域 - 蛋白质相互作用 SAM域的配置和内部动力学。我们将以相同的方式研究特定酪氨酸磷酸化的作用，从而揭示这些功能上重要的翻译后修饰的分子基础。对EPH相关的SAM结构域构象动力学和蛋白质蛋白相互作用的研究改变了我们对域的正常和疾病功能的看法。从这项基础科学研究中获得的知识将成为其他动态蛋白质复合物的一般模型。此外，获得的见解最终可能导致设计诊断和治疗剂。