Allosteric regulation of SERCA by phosphorylation-mediated conformational shift of phospholamban. Proc Natl Acad Sci U S A 2013 Oct 22;110(43):17338-43
Date
10/09/2013Pubmed ID
24101520Pubmed Central ID
PMC3808617DOI
10.1073/pnas.1303006110Scopus ID
2-s2.0-84886402422 (requires institutional sign-in at Scopus site) 109 CitationsAbstract
The membrane protein complex between the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) and phospholamban (PLN) controls Ca(2+) transport in cardiomyocytes, thereby modulating cardiac contractility. β-Adrenergic-stimulated phosphorylation of PLN at Ser-16 enhances SERCA activity via an unknown mechanism. Using solid-state nuclear magnetic resonance spectroscopy, we mapped the physical interactions between SERCA and both unphosphorylated and phosphorylated PLN in membrane bilayers. We found that the allosteric regulation of SERCA depends on the conformational equilibrium of PLN, whose cytoplasmic regulatory domain interconverts between three different states: a ground T state (helical and membrane associated), an excited R state (unfolded and membrane detached), and a B state (extended and enzyme-bound), which is noninhibitory. Phosphorylation at Ser-16 of PLN shifts the populations toward the B state, increasing SERCA activity. We conclude that PLN's conformational equilibrium is central to maintain SERCA's apparent Ca(2+) affinity within a physiological window. This model represents a paradigm shift in our understanding of SERCA regulation by posttranslational phosphorylation and suggests strategies for designing innovative therapeutic approaches to enhance cardiac muscle contractility.
Author List
Gustavsson M, Verardi R, Mullen DG, Mote KR, Traaseth NJ, Gopinath T, Veglia GAuthor
Gopinath Tata PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Allosteric RegulationAmino Acid Sequence
Animals
Calcium
Calcium-Binding Proteins
Kinetics
Lipid Bilayers
Magnetic Resonance Spectroscopy
Membrane Lipids
Models, Molecular
Molecular Sequence Data
Molecular Structure
Mutation
Phosphorylation
Protein Binding
Protein Conformation
Protein Interaction Mapping
Protein Structure, Secondary
Protein Structure, Tertiary
Rabbits
Sarcoplasmic Reticulum Calcium-Transporting ATPases
