title: Sarcolipin Promotes Uncoupling of the SERCA Ca2+Pump by Inducing a Structural Rearrangement in the Energy-Transduction Domain.
abstract: We have performed microsecond (μs) molecular dynamics simulation (MDS) to identify structural mechanisms for sarcolipin (SLN) uncoupling of Ca2+transport from ATP hydrolysis for the sarcoplasmic reticulum Ca2+-ATPase (SERCA). SLN regulates muscle metabolism and energy expenditure to provide resistance against diet-induced obesity and extreme cold. MDS demonstrated that the cytosolic domain of SLN induces a salt bridge-mediated structural rearrangement in the energy-transduction domain of SERCA. We propose that this structural change uncouples SERCA by perturbing Ca2+occlusion at residue E309 in transport site II, thus facilitating Ca2+backflux to the cytosol. Our results have important implications for designing muscle-based therapies for human obesity.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics and ‡Biophysical Technology Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Autry
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics and ‡Biophysical Technology Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: David D
authors.initials: DD
authors.lastname: Thomas
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics and ‡Biophysical Technology Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: L Michel
authors.initials: LM
authors.lastname: Espinoza-Fonseca
mesh_terms: D004734:Energy Metabolism; D009124:Muscle Proteins / Q000737:chemistry*; D011487:Protein Conformation; D011510:Proteolipids / Q000737:chemistry*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000737:chemistry*; D015398:Signal Transduction
chemical_list: D009124:Muscle Proteins; D011510:Proteolipids; C077258:sarcolipin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases