Structural Basis for Sarcolipin's Regulation of Muscle Thermogenesis by the Sarcoplasmic Reticulum Ca-ATPase

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2021 Nov 26

PMID 34826239

Citations 7

Authors

Songlin Wang

Tata Gopinath

Erik K Larsen

Daniel K Weber

Caitlin Walker

Venkateswara Reddy Uddigiri

Kaustubh R Mote

Sanjaya K Sahoo

Muthu Periasamy

Gianluigi Veglia

Affiliations

Soon will be listed here.

Abstract

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.

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