Sarcolipin Promotes Uncoupling of the SERCA Ca2+ Pump by Inducing a Structural Rearrangement in the Energy-Transduction Domain

Joseph M. Autry, David D. Thomas, L. Michel Espinoza-Fonseca

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19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6083-6086
Number of pages4
JournalBiochemistry
Volume55
Issue number44
DOIs
StatePublished - Nov 8 2016

Bibliographical note

Funding Information:
This work was supported by grants to L.M.E.-F. [National Institutes of Health (NIH) Grant R01GM120142 and American Heart Association Grant 12SDG12060656] and D.D.T. (NIH Grant R01GM27906).

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