Allosteric regulation of SERCA by phosphorylation-mediated conformational shift of phospholamban.

Abstract:

: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.

authors

Gustavsson M,Verardi R,Mullen DG,Mote KR,Traaseth NJ,Gopinath T,Veglia G

doi

10.1073/pnas.1303006110

subject

Has Abstract

pub_date

2013-10-22 00:00:00

pages

17338-43

issue

43

eissn

0027-8424

issn

1091-6490

pii

1303006110

journal_volume

110

pub_type

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