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Structural Studies of a T cell Specific Tyrosine Kinase

T 细胞特异性酪氨酸激酶的结构研究

基本信息

批准号：
7649954
负责人：
AMY H ANDREOTTI
金额：
$ 32.89万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-01-15 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7649954
关键词：
Actins Address Area Autoimmunity Binding Biochemical Biological Cells Collaborations Complex Crystallization Cyclophilin A Cytoskeletal Modeling Data Dimerization Disease Docking Ensure Face Family Family member Funding Generations Goals Grant Hematopoietic Immune Immune System Diseases Immune response Immunosuppression In Vitro Kinetics Knowledge Length Link Lymphocyte-Specific p56LCK Tyrosine Protein Kinase Mature T-Lymphocyte Measurable Mediating Membrane Proteins Modeling Molecular Mutation Outcome PH Domain Peptides Peptidylprolyl Isomerase Phosphorylation Phosphorylation Site Phosphotransferases Phosphotyrosine Protein Kinase Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Proteins Reaction Reagent Receptor Protein-Tyrosine Kinases Regulation Research Research Personnel Resolution Role Second Messenger Systems Signal Pathway Signal Transduction Signaling Protein Site Src homology 2 domain-containing, transforming protein 1 Structure T-Cell Receptor T-Lymphocyte TEC Protein Tyrosine Kinase Testing Therapeutic Uses Thinking Time Tyrosine Variant Work base cell mediated immune response gain of function genetic regulatory protein human disease immune function innovation insight interleukin-2 tyrosine kinase kinase inhibitor mutant prevent programs protein complex public health relevance research study second messenger small molecule src Homology Domains src Homology Region 2 Domain src-Family Kinases stem therapeutic target thymocyte tool

项目摘要

DESCRIPTION (provided by applicant): Tyrosine kinase activity is a crucial component of cellular signaling cascades. Precise regulatory control over kinase activity must be maintained during signaling as evidenced by numerous human diseases that arise upon dysregulation of protein kinases. This project is aimed at generating a molecular level understanding of how tyrosine kinase activity is regulated during T cell signaling. The current renewal application continues to focus on the Tec family immunological tyrosine kinase Interleukin-2 tyrosine kinase, Itk. Our work over the last period has generated preliminary data that support mechanistic models for Itk regulation. Specifically, we have identified Itk dimerization as a switch for turning Itk catalytic activity 'off'; we have discovered a specific docking interaction between Itk and its substrates that ensures fidelity in target phosphorylation; and we have data that suggest that the peptidyl prolyl isomerase, cyclophilin A, controls Itk activity by preventing substrate docking. Our studies on Itk and related Tec family members have also extended our understanding of substrate recognition for the well studied Src family of tyrosine kinases. The Src kinase, Lck, activates Itk following TCR engagement by phosphorylating a specific tyrosine in the Itk kinase domain and we have now identified that this reaction occurs via recognition of a remote substrate docking site. The aims proposed in this application will pursue detailed structural studies of all of the protein regulatory complexes described. The molecular level knowledge that will emerge from this work will provide a better understanding of T cell signaling and the means to target specific interactions for therapeutic uses. PUBLIC HEALTH RELEVANCE: This proposal aims to understand specific protein interaction leading to activation of tyrosine kinases in the immune response. The public health relevance of the project relates to developing new ways to either limit or enhance the immune response in the face of autoimmunity, immunosuppression or immunological diseases. Kinases in particular are prime therapeutic targets since they control much of immune cell signaling and genetic defects in specific kinases are linked to specific human diseases.

描述（由申请人提供）：酪氨酸激酶活性是细胞信号级联的关键组成部分。在信号传导过程中，必须保持对激酶活性的精确调控，许多人类疾病都是由蛋白激酶失调引起的。该项目旨在从分子水平上了解酪氨酸激酶活性是如何在T细胞信号传导过程中受到调节的。目前的更新申请继续集中在Tec家族免疫酪氨酸激酶白介素-2酪氨酸激酶（Interleukin-2 tyrosine kinase, Itk）。我们在过去一段时间的工作已经产生了支持Itk调节机制模型的初步数据。具体来说，我们已经确定Itk二聚化是关闭Itk催化活性的开关；我们发现Itk和它的底物之间有一种特定的对接相互作用，可以确保靶磷酸化的保真度；我们有数据表明肽基脯氨酸异构酶，亲环蛋白A，通过阻止底物对接来控制Itk的活性。我们对Itk和相关Tec家族成员的研究也扩展了我们对酪氨酸激酶Src家族的底物识别的理解。Src激酶Lck通过磷酸化Itk激酶结构域的特定酪氨酸来激活TCR后的Itk，我们现在已经确定该反应是通过识别远程底物对接位点发生的。在本申请中提出的目标将对所描述的所有蛋白质调节复合物进行详细的结构研究。从这项工作中产生的分子水平知识将提供对T细胞信号传导的更好理解，以及针对治疗用途的特定相互作用的手段。公共卫生相关性：本提案旨在了解导致免疫反应中酪氨酸激酶激活的特定蛋白质相互作用。该项目的公共卫生相关性涉及开发新的方法，在面对自身免疫、免疫抑制或免疫疾病时限制或增强免疫反应。激酶是主要的治疗靶点，因为它们控制着免疫细胞的信号传导，而特定激酶的遗传缺陷与特定的人类疾病有关。