The sarcomere is the central element of the cardiac cross-bridge cycle and is thus responsible for the heart's contraction. The molecular myosin motor is a target structure for new therapies to increase or reduce the contractility of the sarcomere. The role played by the light chain proteins RLC and ELC, which are integrally associated with myosin, needs to be better understood.
In the present study, the team of Benjamin Meder investigated post-translational mechanisms of ELC and RLC in the human heart for the first time. They found a relationship with cardiac performance, more specifically, ejection fraction. Screening for interaction partners, the protein kinase NEK9 was conspicuous, interacting with and phosphorylating ELC. Using CRISPR-induced mutants and genetic sensitizing experiments, a causal relationship between ELC phosphorylation and cardiac contractility was demonstrated.
The ELC molecule is remarkably adaptable, with nine possible phosphorylation sites, highlighting its central importance in the cross-bridge cycle. The identified NEK9 kinase thus provides a new potential target for therapeutic modulation of the sarcomere, e.g. in dilated cardiomyopathy and heart failure.
October 2022