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NIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart

Müller M, Eghbalian R, Boeckel J-N, Frese KS, Haas J, Kayvanpour E, Sedaghat-Hamedani F, Lackner MK, Tugrul OF, Ruppert T, Tappu R, Martins BD, Kneuer JM, Piekarek A, Herch S, Schudy S, Keller A, Grammes N, Bischof C, Klinke A, Cardoso-Moreira M, Kaessmann H, Katus HA, Frey N, Steinmetz LM, Meder B
Nat Commun. 2022;13:6209. doi:10.1038/s41467-022-33658-2
To adapt to changing hemodynamic demands, regulatory mechanisms modulate actin-myosin-kinetics by calcium-dependent and -independent mechanisms. We investigate the posttranslational modification of human essential myosin light chain (ELC) and identify NIMA-related kinase 9 (NEK9) to interact with ELC. NEK9 is highly expressed in the heart and the interaction with ELC is calcium-dependent. Silencing of NEK9 results in blunting of calcium-dependent ELC-phosphorylation. CRISPR/Cas9-mediated disruption of NEK9 leads to cardiomyopathy in zebrafish. Binding to ELC is mediated via the protein kinase domain of NEK9. A causal relationship between NEK9 activity and ELC-phosphorylation is demonstrated by genetic sensitizing in-vivo. Finally, we observe significantly upregulated ELC-phosphorylation in dilated cardiomyopathy patients and provide a unique map of human ELC-phosphorylation-sites. In summary, NEK9-mediated ELC-phosphorylation is a calcium-dependent regulatory system mediating cardiac contraction and inotropy.
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