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

1133351月亮施加的负荷--即使是处于亚折叠状态的负荷--通过蛋白质传递可以显著改变蛋白质的构象和化学行为，但机械负荷在蛋白质内部如何以及在哪里表现出来的基本细节仍不清楚。鉴于蛋白质的自由能格局和其化学反应势之间的内在二元性，应变能量存储的知识是理解蛋白质耦合的机械力-化学行为的关键；最终掌握着揭示蛋白质中机械转导的基本机制的关键。逐渐增加的恒定载荷被施加到：(I)组成的次要基序，以及(Ii)整个结构域，以洞察主要结构域的结构和振动特征的变化，以及改变的化学行为。了解焦点黏附(FA)蛋白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/调节通路的理解，特别是在疾病情况下，识别潜在的分子靶点，是治疗药物/治疗的关键。所利用的洞察力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蛋白的完全“敲除”相关的系统性问题。

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.