Phospholamban is related to the autoinhibitory domain of the plasma membrane Ca(2+)-pumping ATPase.

The Ca2+ pumps of the plasma membrane (PM ATPase) and of sarcoplasmic reticulum (SR ATPase) share a number of structural and functional properties. A major difference is the regulatory mechanism. The PM ATPase contains a C-terminal autoinhibitory domain; calmodulin binds to it, removing the inhibition. The SR ATPase contains a domain that interacts with the inhibitor protein phospholamban when the latter is in the nonphosphorylated state; phosphorylation of phospholamban removes the inhibition. Peptides corresponding to the autoinhibitory domain of the PM ATPase were synthesized and found to inhibit the SR ATPase. A 28-residue peptide (C28W), containing the entire autoinhibitory domain, was the most powerful (IC50 = 15 microM; lmax greater than 90%). The inhibition was Ca2+ dependent and more pronounced at submicromolar Ca2+ concentrations. C28W is about 50% homologous to the cytosolic domain of phospholamban, the hydrophilic portion of which was found to interact directly with calmodulin (Kd = about 700 nM). However, while calmodulin reversed the inhibition of the SR ATPase by C28W, it failed to reverse that induced by nonphosphorylated phospholamban.