Functional and physical competition between phospholamban and its mutants provides insight into the molecular mechanism of gene therapy for heart failure

► LOF mutants of PLB can compete with WT-PLB and relieve SERCA inhibition. ► Competition measured by both ATPase activity and FRET. ► For PLB and its mutants, inhibitory potency is distinct from SERCA affinity. ► Explains partial success of S16E-PLB gene therapy in heart failure animal models. ► Method for testing PLB mutant candidates for heart failure gene therapy.