Proc. Natl. Acad. Sci. USA, doi:10.1073/pnas.1303006110

Credit: MARTIN GUSTAVSSON & GIANLUIGI VEGLIA

The contraction of muscle cells occurs when Ca2+ ions are released from the sarcoplasmic reticulum and ceases when those ions are resequestered by the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Phospholamban (PLN), a small integral membrane protein, inhibits SERCA activity in vivo; the phosphorylation of PLN by protein kinase A alleviates SERCA inhibition. Gustavsson et al. now report that the conformational dynamics of PLN have an important role in this process. In the absence of SERCA, the regulatory Ia domain of PLN exists in two major conformational states: a helical, membrane-associated 'T' state and a disordered, membrane-unassociated 'R' state. The authors used solid-state NMR spectroscopy to show that phosphorylation of PLN shifts the equilibrium from the R state toward a third, SERCA-bound ('B') state, which is sparsely populated when PLN is not phosphorylated. Although the large size of the phospho-PLN–SERCA complex (∼116 kDa) prevented the authors from using NMR spectroscopy to determine its atomic structure, they were able to show that the phosphate group of phospho-PLN binds an allosteric site between SERCA's nucleotide-binding and phosphorylation domains. Additional work is needed to determine exactly how the structure of the active phospho-PLN–SERCA complex differs from that of the inactive PLN–SERCA complex.