Cardiac myosin light chain 1 dependent regulatory mechanisms in dilated cardiomyopathy

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The essential myosin light chain (cMLC-1) as part of the sarcomere is closely interacting with motor-myosin. As shown by the applicant, cMLC-1 can be phosphorylated at two highly conserved phosphorylation sites, Thr64 and Ser195. Lack of the phosphorylation site at Ser195 causes severely impaired cardiac contractility in a genetic zebrafish model, hinting at a pivotal role in sarcomere function. However, the contribution and precise regulation of cMLC-1 in dilated cardiomyopathy or heart failure is unknown.The proposed research aims to unravel the functional relevance of cMLC-1 posttranslational phosphorylation and the associated regulatory pathways and dissect its contribution to human heart disease. We aim to identify and validate cMLC-1 interaction partners in vitro with special focus on kinases and phosphatases responsible for its posttranslational modification. The knowledge about direct interaction partners will be used to define underlying regulatory pathways as well as modes of activation and inhibition, a preamble for potential therapeutic translation. In a next step towards therapeutic modulation, the functional consequence of altered cMLC-1 regulation is investigated in vivo. We will explore the biological significance of genetic alterations and posttranslational modifications of cMLC-1 as well as the identified interaction partners on heart function in engineered transgenic zebrafish models. Elucidating the molecular properties of cMLC-1 will help to deepen our basic understanding of sarcomere function and define targets for molecular treatment strategies of cardiomyopathy and heart failure.