Mechanical Regulation of Actin Binding Proteins

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Project Summary PI: Daniel Fletcher, Ph.D. NIH R01 Administrative Supplement Project Title: Mechanical Regulation of Actin Binding Proteins Project Period: 7/25/2019 – 4/30/2023 The actin cytoskeleton consists of spatially organized structures of filaments that are architecturally distinct and formed from over 300 different actin-binding proteins. One of the key roles of actin networks in cells is to generate, transmit, and resist physical forces, but whether the forces carried by actin filaments influence the binding of actin-binding proteins is not well understood. This project is investigating the ability of tandem calponin- homology domains (CH1-CH2) to bind actin filaments in a tension-dependent manner, and it will explore the functional impact of tension-dependent binding through a set of in vitro and live cell experiments. The requested FRET-FLIM attachment will provide a way to test our hypothesis that tension-dependent changes in actin filaments can alter protein binding affinity by relieving the steric inhibition at the binding interface. The outcome of this work will be a new understanding of how force can organize actin networks and influence the function of both healthy and diseased cells.