Zhou Jing, Aponte-Santamaría Camilo, Sturm Sebastian, Bullerjahn Jakob Tómas, Bronowska Agnieszka, Gräter Frauke
Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
Leipzig University, Institute for Theoretical Physics, Leipzig, Germany.
PLoS Comput Biol. 2015 Nov 6;11(11):e1004593. doi: 10.1371/journal.pcbi.1004593. eCollection 2015 Nov.
Mechanosensing at focal adhesions regulates vital cellular processes. Here, we present results from molecular dynamics (MD) and mechano-biochemical network simulations that suggest a direct role of Focal Adhesion Kinase (FAK) as a mechano-sensor. Tensile forces, propagating from the membrane through the PIP2 binding site of the FERM domain and from the cytoskeleton-anchored FAT domain, activate FAK by unlocking its central phosphorylation site (Tyr576/577) from the autoinhibitory FERM domain. Varying loading rates, pulling directions, and membrane PIP2 concentrations corroborate the specific opening of the FERM-kinase domain interface, due to its remarkably lower mechanical stability compared to the individual alpha-helical domains and the PIP2-FERM link. Analyzing downstream signaling networks provides further evidence for an intrinsic mechano-signaling role of FAK in broadcasting force signals through Ras to the nucleus. This distinguishes FAK from hitherto identified focal adhesion mechano-responsive molecules, allowing a new interpretation of cell stretching experiments.
粘着斑处的力感知调节着重要的细胞过程。在此，我们展示了分子动力学（MD）和机械生化网络模拟的结果，这些结果表明粘着斑激酶（FAK）作为一种机械传感器具有直接作用。从膜通过FERM结构域的PIP2结合位点以及从细胞骨架锚定的FAT结构域传播的拉力，通过将其中心磷酸化位点（Tyr576/577）从自抑制性FERM结构域解锁来激活FAK。由于与单个α-螺旋结构域和PIP2-FERM连接相比，其机械稳定性显著较低，不同的加载速率、牵拉方向和膜PIP2浓度证实了FERM-激酶结构域界面的特定打开。对下游信号网络的分析为FAK在通过Ras向细胞核传递力信号方面的内在机械信号作用提供了进一步证据。这将FAK与迄今已鉴定的粘着斑机械响应分子区分开来，从而对细胞拉伸实验有了新的解释。
