S019 Improving Cardiac Ca 2+ Transport into the Sarcoplasmic Reticulum in Heart Failure: Lessons from the Ubiquitous Serca2b Ca 2+ Pump

The diminished cardiac contractility in heart failure (HF) can partially be explained by a reduced activity of the cardiac sarco(endo)plasmic reticulum Ca 2+-ATPase SERCA2a. Improving its function is a potential strategy to improve cardiac contractility and reverse remodeling. This might be achieved by increasing SERCA2a's affinity for Ca 2+. Compared to SERCA2a, the ubiquitous SERCA2b isoform displays a twofold higher apparent Ca 2+ affinity because of an alternative C-terminus (2b-tail) containing an extra transmem-brane segment (TM11) and luminal extension. Here, the molecular mechanism of the 2b-tail was explored to understand how it controls the Ca 2+ affinity. By characterizing SERCA2b mutants and SERCA1a2b chimera, we demonstrated that the luminal extension interacts with luminal loops of the pump, stabilizing the Ca 2+-bound E1 conformation and increasing the apparent Ca 2+ affinity. In addition, peptides corresponding to TM11 functionally interact with purified SERCA1a in reconstituted vesicles, providing evidence for TM11 as a distinct functional region. Based on our NMR structure of TM11, a structural model was proposed for TM11 interaction on helices TM7 and TM10 of the pump, resembling the interaction of the β-subunit interaction with Na + ,K +-ATPase. The 2b-tail site may represent a novel target to improve SERCA2a's apparent Ca 2+ affinity in HF, distinct from the better-described phospholamban site.