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

1133351moon施加的载荷-即使是在次展开状态下？通过蛋白质传递可以显著改变蛋白质的构象和化学行为，但机械负荷如何以及在何处在蛋白质中表现出来的基本细节仍不清楚。考虑到蛋白质的自由能及其化学反应势之间的内在对偶性，应变能量存储的知识是理解蛋白质耦合力学-化学行为的关键；最终掌握了揭示蛋白质机械转导基本机制的关键。为了达到这些目的，通过定向分子动力学模拟研究了Focal Adhesion Kinase （FAK）的三个主要域内的负载传输。越来越高的恒定载荷被应用于：(i)组成的次级基序，（ii）整个结构域，以深入了解结构和振动特性的变化，以及主要结构域化学行为的改变。作为肿瘤发生、转移和生存信号传导的关键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。了解局灶黏附蛋白（FA）如何在信号传递中发挥其假定的作用，对于促进对各种信号/调节途径的理解，特别是在疾病的情况下，对于确定治疗剂/治疗的潜在分子“靶点”至关重要。所利用的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，这些靶点是专门设计的，以避免与FAK等重要FA蛋白完全“敲除”相关的系统性问题。除了FAK之外，还解释了依赖于机械负荷的细胞信号/调节途径的一些基本操作原理。

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.