| Literature DB >> 36266340 |
Marion Müller1,2,3, Rose Eghbalian1,2, Jes-Niels Boeckel4, Karen S Frese2,5, Jan Haas2,5, Elham Kayvanpour2,5, Farbod Sedaghat-Hamedani2,5, Maximilian K Lackner2,5, Oguz F Tugrul2,5, Thomas Ruppert6,7, Rewati Tappu2,5, Diana Martins Bordalo2,5, Jasmin M Kneuer4, Annika Piekarek5, Sabine Herch5, Sarah Schudy2,5, Andreas Keller8,9, Nadja Grammes8,9, Cornelius Bischof3, Anna Klinke3, Margarida Cardoso-Moreira7, Henrik Kaessmann7, Hugo A Katus2,5, Norbert Frey2,5, Lars M Steinmetz2,10, Benjamin Meder11,12,13.
Abstract
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.Entities:
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Year: 2022 PMID： 36266340 PMCID： PMC9585074 DOI： 10.1038/s41467-022-33658-2
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 17.694