Structural dynamics and topology of phosphorylated phospholamban homopentamer reveal its role in the regulation of calcium transport

Vitaly V. Vostrikov, Kaustubh R. Mote, Raffaello Verardi, Gianluigi Veglia

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Phospholamban (PLN) inhibits the sarco(endo)plasmic reticulum Ca 2+-ATPase (SERCA), thereby regulating cardiac diastole. In membranes, PLN assembles into homopentamers that in both the phosphorylated and nonphosphorylated states have been proposed to form ion-selective channels. Here, we determined the structure of the phosphorylated pentamer using a combination of solution and solid-state nuclear magnetic resonance methods. We found that the pinwheel architecture of the homopentamer is preserved upon phosphorylation, with each monomer having an L-shaped conformation. The TM domains form a hydrophobic pore approximately 24 Å long and 2 Å in diameter, which is inconsistent with canonical Ca2+-selective channels. Phosphorylation, however, enhances the conformational dynamics of the cytoplasmic region of PLN, causing partial unwinding of the amphipathic helix. We propose that PLN oligomers act as storage for active monomers, keeping SERCA function within a physiological window.

Original languageEnglish (US)
Pages (from-to)2119-2130
Number of pages12
JournalStructure
Volume21
Issue number12
DOIs
StatePublished - Dec 3 2013

Bibliographical note

Funding Information:
The authors thank Dr. Martin Gustavsson for helpful discussions, and Drs. Lucia Becucci and Rolando Guidelli for sharing electrochemistry data prior to publication. ssNMR data were acquired at the Minnesota NMR Center and NHMFL. Relaxation data at 750 MHz were acquired at NMRFAM. Structure calculation utilized computing resources at the University of Minnesota Supercomputing Institute. This work was supported by a grant from the National Institutes of Health (GM64742 to G.V.) and a postdoctoral fellowship from the American Heart Association (13POST14670054 to V.V.).

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