The determination of the first crystal structures of heart-specific SERCA2a provides a structural basis for understanding its distinct regulation and potential as a therapeutic target in heart failure.
May guide SERCA2a-targeted therapies in heart failure; leaves open translation to human cardiac outcomes.
The isoform 2a of sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA2a) performs active reuptake of cytoplasmic Ca 2+ and is a major regulator of cardiac muscle contractility. Dysfunction or dysregulation of SERCA2a is associated with heart failure, while restoring its function is considered as a therapeutic strategy to restore cardiac performance, but its structure was not yet determined. Based on native, active protein purified from pig ventricular muscle, we present the first crystal structures of SERCA2a that were determined in the CPA-stabilized and H + -occluded [H 2-3 ]E2-AlF 4 - (3.3 Å) form, arranged as parallel dimers, and the Ca 2+ -occluded [Ca 2 ]E1-ATP (4.0 Å) form. We compare these new structures to similar forms of the skeletal muscle SERCA1a and address structural, functional and regulatory differences. We show that the isoform specific motifs of SERCA2a allow a distinct regulation by post-translational modifications and affect the dynamic behavior, which may explain specific properties and regulation.
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Sitsel et al. (2018) studied this question.
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