Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation

Phospholamban (PLN) is a mini-membrane protein that directly controls the cardiac Ca2+-transport response to beta-adrenergic stimulation, thus modulating cardiac output during the fight-or-flight response. In the sarcoplasmic reticulum membrane, PLN binds to the sarco(endo) plasmic reticulum Ca2+ -ATPase (SERCA), keeping this enzyme's function within a narrow physiological window. PLN phosphorylation by cAMP-dependent protein kinase A or increase in Ca2+ concentration reverses the inhibitory effects through an unknown mechanism. Using oriented-sample solid-state NMR spectroscopy and replica-averaged NMR-restrained structural refinement, we reveal that phosphorylation of PLN's cytoplasmic regulatory domain signals the disruption of several inhibitory contacts at the transmembrane binding interface of the SERCA-PLN complex that are propagated to the enzyme's active site, augmenting Ca2+ transport. Our findings address longstanding questions about SERCA regulation, epitomizing a signal transduction mechanism operated by posttranslationally modified bitopic membrane proteins.

Automated summary

Phospholamban (PLN) regulates cardiac Ca2+ transport response by phosphorylation or increased Ca2+ concentration, disrupting inhibitory contacts on the SERCA binding interface and enhancing Ca2+ transport. This study sheds light on the signal transduction mechanism operated by posttranslationally modified bitopic membrane proteins, addressing longstanding questions about SERCA regulation.