Towards a Fundamental Understanding of the Mechanisms of Mechanotransduction Through Focal Adhesion Proteins

通过焦点粘附蛋白对力传导机制有一个基本的了解

• 批准号: 1133351
• 负责人: Tess Moon
• 金额: $ 33万
• 依托单位: University of Texas at Austin
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1133351&HistoricalAwards=false
• 关键词: Towards; Fundamental; Understanding; Mechanisms; Mechanotransduction

1133351MoonApplied loads - even those in the sub-unfolding regime?transmitted through proteins can significantly alter the proteins - conformations and chemical behavior, yet essential details of how and where mechanical load manifests itself inside proteins remain unclear. Given the intrinsic duality between a protein's free energy landscape and its chemical reactive potential, knowledge of strain energy storage is key to understanding of the coupled mechano-chemo behavior of proteins; ultimately holding the key to unveiling the fundamental mechanisms of mechanotransduction in proteins. Towards these ends, load transmissions within the three major domains of Focal Adhesion Kinase (FAK) are studied via steered molecular dynamics simulations. Progressively higher constant loads are applied to: (i) constituent secondary motifs, and (ii) entire domains, to provide insight into the changes in structural and vibrational characteristics, as well as the altered chemical behavior, of the major domains. As a key regulator of cellular processes central to tumorigenesis, metastasis and survival signaling, FAK has been identified as a potential target for anti-cancer drugs. Knowledge of how focal adhesion (FA) proteins perform their presumed roles in signal transmission is key to advancing the understanding of various signaling/regulatory pathways and, particularly in case of disease, to identifying potential molecular "targets" for therapeutic agents/treatments. Insights harnessed will help identify viable - perhaps even mechanically induced - targets for chemotherapy that are specifically designed to avoid systemic issues associated with complete "knock-out" of vital FA proteins like FAK. Beyond FAK, some of the basic operating principles underlying cellular signaling/regulatory pathways reliant on mechanical load are explained.

1133351施加的月球载荷-即使是在亚展开状态下？通过蛋白质传递的机械载荷可以显著改变蛋白质的构象和化学行为，但是关于机械载荷在蛋白质内部如何以及在何处表现的基本细节仍然不清楚。鉴于蛋白质的自由能景观和其化学反应潜力之间的内在二元性，应变能量存储的知识是理解蛋白质的耦合机械化学行为的关键;最终掌握揭示蛋白质中机械转导的基本机制的关键。为了实现这些目标，通过转向分子动力学模拟研究了粘着斑激酶（FAK）的三个主要领域内的负载传输。逐渐更高的恒定载荷施加到：（i）构成次级基序，和（ii）整个域，以提供对主要域的结构和振动特性的变化以及改变的化学行为的洞察。作为肿瘤发生、转移和存活信号传导的细胞过程的关键调节因子，FAK已被确定为抗癌药物的潜在靶点。粘着斑（FA）蛋白如何在信号传递中发挥其假定作用的知识是促进理解各种信号传导/调节途径的关键，特别是在疾病的情况下，是识别治疗剂/治疗的潜在分子“靶标”的关键。利用这些见解将有助于确定可行的-甚至可能是机械诱导的-化疗靶点，这些靶点专门设计用于避免与完全“敲除”重要FA蛋白（如FAK）相关的全身性问题。除了FAK之外，还解释了依赖于机械负荷的细胞信号传导/调节途径的一些基本操作原理。