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Alpha-catenin function in cardiomyocyte adhesion and cytoskeletal organization

α-连环蛋白在心肌细胞粘附和细胞骨架组织中的功能

基本信息

批准号：
10671042
负责人：
Adam Vincent Kwiatkowski
金额：
$ 38.93万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671042
关键词：
Actin-Binding Protein Actins Adaptor Signaling Protein Adherens Junction Adhesions Adhesives Affect Allosteric Regulation Architecture Binding Biochemical Biochemistry Biological Cadherins Cardiac Myocytes Cardiomyopathies Cell Adhesion Cell Communication Cell-Cell Adhesion Cells Cellular biology Collection Complex Coupling Cues Cytoskeletal Filaments Cytoskeletal Modeling Cytoskeletal Proteins Cytoskeleton Data Desmosomes Development Epithelium Equilibrium Experimental Designs Extracellular Matrix Foundations Goals Grant Health Heart Heart Diseases Homeostasis Human In Situ Individual Intercalated disc Intermediate Filaments Knowledge Lead Ligand Binding Ligands Link Maintenance Mechanics Mediating Membrane Microfilaments Molecular Mutation Myofibrils Outcome Output Peripheral Property Proteins Proteomics Publishing Research Role Series Signal Transduction System Testis Thermodynamics Tissues Vinculin Work alpha catenin cardiogenesis heart function insight link protein mechanical force mechanical signal novel therapeutic intervention operation protein complex reconstitution recruit resilience response tool transmission process

项目摘要

Project Summary With every heartbeat, the junctional complexes that couple cardiomyocytes must transmit the mechanical forces of contraction while maintaining adhesive homeostasis. Cardiomyocytes are linked end-to-end by the intercalated disc (ICD), a specialized junction that coordinates cell signaling, electrical and mechanical operations. The ICD comprises adherens junctions (AJs) and desmosomes that connect the actin and intermediate filament cytoskeletons, respectively, of adjoining cells. ICD function requires multiple adhesion and cytoskeletal proteins and mutations in these proteins are linked to cardiomyopathies. However, relatively little is known about how adhesion complexes are regulated to establish and maintain heart tissue integrity. The core of the adherens junction is the cadherin-catenin complex, which is connected to the actin cytoskeleton through a-catenin. a-Catenin is a multifunctional, mechanoresponsive actin-binding protein that localizes to the cardiomyocyte ICD. However, a-catenin functions in cell-cell adhesion in cardiomyocytes are poorly understood. Our objective in this application is to determine how mechanical and molecular inputs are transduced through the two a-catenins expressed in the human heart – aE(Epithelial)-catenin and aT(Testes)- catenin – to regulate cardiomyocyte adhesion. Our rationale is that defining the individual and collective roles of a-catenin at cardiomyocyte AJs will provide fundamental insight into how cardiomyocyte AJs balance mechanical and signaling functions. We hypothesize that aE-catenin and aT-catenin form unique cadherin- catenin complexes in response to cellular cues to function as mechanical checkpoints for ICD assembly and cardiomyocyte organization. In this proposal, we seek to: 1) define the allosteric mechanisms that regulate a- catenin ligand binding at the cardiomyocyte AJ; 2) determine how ligand recruitment to a-catenin promotes AJ assembly and cytoskeletal attachment; and 3) identify how external mechanical cues regulate AJ organization. Knowledge to be gained through our studies include a detailed, mechanistic understanding of how a-catenin molecular properties are tuned for adhesion in cardiomyocytes; how unique molecular complexes are built along the cardiomyocyte AJ to establish and maintain adhesion; and how external mechanical cues feed into the cardiomyocyte AJ to drive organization. This comprehensive, multiscale analysis will develop new tools and acquire new knowledge about the molecular mechanisms of cell adhesion in cardiomyocytes. Understanding the fundamental mechanisms of cell adhesion in cardiomyocytes is necessary for determining how mutations in ICD proteins lead to heart disease and inform the development of new strategies for the treatment of cardiomyopathies.

项目概要每次心跳时，连接心肌细胞的连接复合体必须传递机械力收缩力，同时保持粘附稳态。心肌细胞通过端对端相连闰盘 (ICD)，一种协调细胞信号、电气和机械信号的特殊连接点运营。 ICD 包括粘附连接 (AJ) 和桥粒，它们连接肌动蛋白和分别是相邻细胞的中间丝细胞骨架。 ICD功能需要多次粘合细胞骨架蛋白和这些蛋白的突变与心肌病有关。不过，相对关于如何调节粘附复合物以建立和维持心脏组织完整性，人们知之甚少。粘附连接的核心是钙粘蛋白-连环蛋白复合物，它与肌动蛋白相连通过α-连环蛋白形成细胞骨架。 α-连环蛋白是一种多功能、机械反应性肌动蛋白结合蛋白，定位于心肌细胞 ICD。然而，α-连环蛋白在心肌细胞细胞粘附中的功能是不太了解。我们在此应用中的目标是确定机械和分子输入如何通过人类心脏中表达的两种 a-连环蛋白 – aE（上皮）-连环蛋白和 aT（睾丸）- 转导连环蛋白 - 调节心肌细胞粘附。我们的理由是定义个人和集体的角色心肌细胞 AJ 中的 a-连环蛋白将为了解心肌细胞 AJ 如何平衡提供基础见解机械和信号功能。我们假设 aE-连环蛋白和 aT-连环蛋白形成独特的钙粘蛋白- 连环蛋白复合物响应细胞信号，充当 ICD 组装的机械检查点心肌细胞组织。在本提案中，我们寻求：1）定义调节a-的变构机制连环蛋白配体结合在心肌细胞 AJ 上； 2) 确定α-连环蛋白的配体募集如何促进 AJ 组装和细胞骨架附着； 3) 确定外部机械线索如何调节 AJ 组织。通过我们的研究获得的知识包括对α-连环蛋白如何调整分子特性以适应心肌细胞的粘附；独特的分子复合物是如何构建的沿着心肌细胞AJ建立并维持粘附；以及外部机械线索如何输入心肌细胞 AJ 驱动组织。这种全面的多尺度分析将开发新工具并获得有关心肌细胞细胞粘附分子机制的新知识。了解心肌细胞细胞粘附的基本机制对于确定 ICD 蛋白突变如何导致心脏病并为新策略的开发提供信息治疗心肌病。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

αT-Catenin Is a Constitutive Actin-binding α-Catenin That Directly Couples the Cadherin·Catenin Complex to Actin Filaments.

α-T-连环蛋白是一种组成型肌动蛋白结合 α-连环蛋白，可直接将钙粘蛋白·连环蛋白复合物与肌动蛋白丝偶联。

DOI：
10.1074/jbc.m116.735423
发表时间：
2016
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Wickline,EmilyD;Dale,IanW;Merkel,ChelseaD;Heier,JonathonA;Stolz,DonnaB;Kwiatkowski,AdamV
通讯作者：
Kwiatkowski,AdamV

Mechanical stability of αT-catenin and its activation by force for vinculin binding.

αT-连环蛋白的机械稳定性及其通过强力激活纽蛋白结合。