Structural basis for sarcolipin’s regulation of muscle thermogenesis by the sarcoplasmic reticulum Ca <sup>2+</sup> -ATPase
Songlin Wang, Tata Gopinath, Erik K. Larsen, Daniel K. Weber, Caitlin Walker, Venkateswara Reddy Uddigiri, Kaustubh R. Mote, Sanjaya Kumar Sahoo, Muthu Periasamy, Gianluigi Veglia
Abstract
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.