The Mechanism of Uncoupling ATP Hydrolysis and Calcium Transport in Serca by Sarcolipin

Abstract

The interactions of sarcolipin (SLN) with the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) causes uncoupling of SERCA's ATP hydrolysis and Ca2+ -transport activities. SERCA is an integral component of proper muscle function. It is one of the key proteins responsible for re-establishing the low cytosolic Ca2+ concentrations needed for normal muscle contraction. When SLN is bound to SERCA, fewer moles of Ca2+ are transported per mole of ATP hydrolyzed, which leads to an increase in the heat released. By using solid-state nuclear magnetic resonance spectroscopy and functional assays, we demonstrate that it is the topological coupling between these proteins that is important for the regulation of SERCA. It is through the interactions of their transmembrane regions as well as the interactions of SLN's lumenal tail that lead to uncoupling. These results also provide insight into the mechanism for non-shivering, muscle-based thermogenesis.