Mechanosensitive Conformation of Vinculin Regulates Its Binding to MAPK1
Abstract
Extracellular matrix stiffness sensing by living cells is known to play a major role in a variety of cell mechanobiological processes, such as migration and differentiation. Various membrane and cytoplasmic proteins are involved in transmitting and transducing environmental signals to biochemical cascades. Protein kinases play a key role in regulating the activity of focal adhesion proteins. Recently, an interaction between mitogen-activated protein kinase (MAPK1) and vinculin was experimentally shown to mediate this process. Here, we adopt a molecular modeling approach to further investigate this interaction and its possible regulatory effects. Using a combination of data-driven flexible docking and molecular dynamics simulations guided by previous experimental studies, we predict the structure of the MAPK1-vinculin complex. Furthermore, by comparing the association of MAPK1 with open versus closed vinculin, we demonstrate that MAPK1 exhibits preferential binding toward the open conformation of vinculin, suggesting that the MAPK1-vinculin interaction is conformationally selective. Finally, we demonstrate that changes in the size of the D3-D4 cleft provide a structural basis for the conformational selectivity of the interaction.
References
Raver1, a dual compartment protein, is a ligand for PTB/hnRNPI and microfilament attachment proteins
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