Teilprojekt 6: Analysis of mutually exclusive actin complexes with intrinsically disordered RPEL and WH2 regions

Cytoskeletal actin in mammalian cells is tightly regulated by actin binding proteins. Many of these contain intrinsically disordered regions, such as WH2 regions and the RPEL motifs of the myocardin-related transcription factors (MRTF-A and -B). As a consequence, mutually exclusive binding regulates MRTF-controlled transcription. However, little is known about the factors and modulators which affect IDR-binding during signalling. Within this project, we will investigate which proteins containing WASP-homology 2 (WH2) regions compete with MRTF for G-Actin binding upon stimulation. Further, we will address in which subcellular compartment and when the competition between MRTF’s RPEL motifs and WH2 regions occurs in cells. Finally, we will mechanistically analyse the binding of the intrinsically disordered RPEL and WH2 regions to G-Actin in vitro, and ask whether we can modulate this interaction by small molecules. The identification of small molecule modifiers for MRTF activity is direly needed to better understand its (patho-)physiological function. Our study may pave the way to develop modulators of MRTF-dependent diseases, such as fibrosis and metastasis.