Allosteric Regulation of the Sarcoplasmic Reticulum Ca2+-ATPase by Phospholamban and Sarcolipin using Solid-State NMR Spectroscopy

The membrane protein complexes between the sarcoplasmic reticulum Ca2+-ATPase (SERCA) and phospholamban (PLN) or sarcolipin (SLN) control Ca2+ transport in cardiomyocytes, thereby modulating cardiac muscle contractility. Both PLN and SLN are phosphorylated upon o-adrenergic-stimulated phosphorylation and up-regulate the ATPase via an unknown mechanism. Using solid-state NMR spectroscopy, we mapped the interactions between SERCA and both PLN and SLN in membrane bilayers. We found that the allosteric regulation of the ATPase depends on the conformational equilibria of these two endogenous regulators that maintain SERCA's apparent Ca2+ affinity within a physiological window. Here, we present new regulatory models for both SLN and PLN that represent a paradigm-shift in our understanding of SERCA function. Our data suggests new strategies for designing innovative therapeutic approaches to enhance cardiac muscle contractility.