Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 118, Issue 8, Pages 2124-2133Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jp500316s
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Funding
- NIGMS/NIH [GM108026, R01 GM080542]
- NSF [CHE-1011909, MRI-0722403]
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1305664] Funding Source: National Science Foundation
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Phospholamban (PLB) is a membrane protein that regulates heart muscle relaxation rates via interactions with the sarcoplasmic reticulum Ca2+ ATPase (SERCA). When PLB is phosphorylated or Arg9Cys (R9C) is mutated, inhibition of SERCA is relieved. C-13 and N-15 solid-state NMR spectroscopy is utilized to investigate conformational changes of PLB upon phosphorylation and R9C mutation. C-13=O NMR spectra of the cytoplasmic domain reveal two alpha-helical structural components with population changes upon phosphorylation and R9C mutation. The appearance of an unstructured component is observed on domain Ib. N-15 NMR spectra indicate an increase in backbone dynamics of the cytoplasmic domain. Wild-type PLB (WT-PLB), Ser16-phosphorylated PLB (P-PLB), and R9C-mutated PLB (R9C-PLB) all have a very dynamic domain Ib, and the transmembrane domain has an immobile component. N-15 NMR spectra indicate that the cytoplasmic domain of R9C-PLB adopts an orientation similar to P-PLB and shifts away from the membrane surface. Domain Ib (Leu28) of P-PLB and R9C-PLB loses the alignment. The R9C-PLB adopts a conformation similar to P-PLB with a population shift to a more extended and disordered state. The NMR data suggest the more extended and disordered forms of PLB may relate to inhibition relief.
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