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: 8918698
• 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/8918698
• 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; 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; Solutions; 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）：该拟议项目旨在开发最新的范例，即蛋白质复合物即使不是高度动态的实体，也可以是多配置的。需要了解这种动态复合物的生物物理和功能特征。我们选择涉及 Eph 家族 SAM 结构域的异二聚体复合物作为示例。 SAM 结构域很重要，因为它们存在于 200 多种人类蛋白质中，尤其是人类 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发挥作用，最近的研究表明，EphA2 的 SAM 结构域在多种人类肿瘤和白内障中发生突变，两者都与 EphA2 失调有关。然而，EphA2 SAM 结构域正常和异常功能的分子基础尚不清楚。我们将使用生物物理、计算和细胞生物学方法等三管齐下的方法来表征 EphA1-SHIP2 和 EphA2-SHIP2 SAM:SAM 复合物的多构型特征。此外，我们将研究肿瘤相关突变如何不仅影响蛋白质折叠、稳定性和聚集，还可能通过改变 SAM 结构域-蛋白质相互作用来影响 SAM 域的配置和内部动态。我们将以同样的方式研究特定酪氨酸磷酸化的影响，揭示这些功能上重要的翻译后修饰的分子基础。对 Eph 相关 SAM 结构域构象动力学和蛋白质-蛋白质相互作用的研究改变了我们对该结构域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作为其他动态蛋白质复合物的通用模型。此外，所获得的见解最终可能导致诊断和治疗药物的设计。