Faculty Collaboration Database

Structural basis for sarcolipin's regulation of muscle thermogenesis by the sarcoplasmic reticulum Ca²⁺-ATPase. Sci Adv 2021 Nov 26;7(48):eabi7154

Date

11/27/2021

Pubmed ID

34826239

Pubmed Central ID

PMC8626070

DOI

10.1126/sciadv.abi7154

Scopus ID

2-s2.0-85120338258 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

The sarcoplasmic reticulum (SR) Ca²⁺-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 Ca²⁺ 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.

Author List

Wang S, Gopinath T, Larsen EK, Weber DK, Walker C, Uddigiri VR, Mote KR, Sahoo SK, Periasamy M, Veglia G

Author

Gopinath Tata PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin