Structural basis for sarcolipin's regulation of muscle thermogenesis by the sarcoplasmic reticulum Ca 2+ -ATPase

The sarcoplasmic reticulum (SR) Ca -ATPase (SERCA) plays a central role in muscle contractility and nonshivering thermogenesis. SERCA is regulated by sarcolipin (SLN), a single-pass membrane protein that uncouples Ca transport from ATP hydrolysis, promoting futile enzymatic cycles and heat generatio...

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Bibliographic Details
Published in:Science advances 2021-11, Vol.7 (48), p.eabi7154
Main Authors: Wang, Songlin, Gopinath, Tata, Larsen, Erik K, Weber, Daniel K, Walker, Caitlin, Uddigiri, Venkateswara Reddy, Mote, Kaustubh R, Sahoo, Sanjaya K, Periasamy, Muthu, Veglia, Gianluigi
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Language:English
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Summary:The sarcoplasmic reticulum (SR) Ca -ATPase (SERCA) plays a central role in muscle contractility and nonshivering thermogenesis. SERCA is regulated by sarcolipin (SLN), a single-pass membrane protein that uncouples Ca transport from ATP hydrolysis, promoting futile enzymatic cycles and heat generation. The molecular determinants for regulating heat release by the SERCA/SLN complex are unclear. Using thermocalorimetry, chemical cross-linking, and solid-state NMR spectroscopy in oriented phospholipid bicelles, we show that SERCA’s functional uncoupling and heat release rate are dictated by specific SERCA/SLN intramembrane interactions, with the carboxyl-terminal residues anchoring SLN to the SR membrane in an inhibitory topology. Systematic deletion of the carboxyl terminus does not prevent the SERCA/SLN complex formation but reduces uncoupling in a graded manner. These studies emphasize the critical role of lipids in defining the active topology of SLN and modulating the heat release rate by the SERCA/SLN complex, with implications in fat metabolism and basal metabolic rate.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abi7154