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Clarification of the physical mechanism by which mutation, is due to dissociation of PLB from SERCA, in a dynamic binding equilibrium, which doi:10.1016/j.jmb.2006.02.051Introduction Phospholamban (PLB)1 is a 52 residue integral membrane protein that regulates the enzymatic activity of sarco-endoplasmic reticulum Ca-ATpase (SERCA) in cardiac sarcoplasmic reticulum (SR).1 The SERCA–PLB calcium-regulatory system has been implicated in cardiovascular disease.2–7 PLB regulates SERCA is needed to develop strategies for rescuing the failing heart muscle. Relief of inhibition does not require PLB dissociation from SERCA It has been suggested that relief of inhibition, due to phosphorylation of PLB, micromolar [Ca2C], or*Corresponding author0022-2836/ $- see front matter q 2006