期刊
PLOS COMPUTATIONAL BIOLOGY
卷 11, 期 11, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pcbi.1004593
关键词
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资金
- Klaus Tschira Foundation
- BMBF SYSTEC programme
- Deutsche Forschungsgemeinschaft (DFG) research group FOR 1543
- BIOMS programme at Heidelberg University
- European Union
- Free State of Saxony
- DFG through FOR 877
- Leipzig School of Natural Sciences - Building with Molecules and Nano-objects (BuildMoNa)
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.
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