Structures of the excited states of phospholamban and shifts in their populations upon phosphorylation

Research output: Contribution to journalJournal articleResearchpeer-review

  • Alfonso De Simone
  • Gustavsson, Martin
  • Rinaldo W Montalvao
  • Lei Shi
  • Gianluigi Veglia
  • Michele Vendruscolo

Phospholamban is an integral membrane protein that controls the calcium balance in cardiac muscle cells. As the function and regulation of this protein require the active involvement of low populated states in equilibrium with the native state, it is of great interest to acquire structural information about them. In this work, we calculate the conformations and populations of the ground state and the three main excited states of phospholamban by incorporating nuclear magnetic resonance residual dipolar couplings as replica-averaged structural restraints in molecular dynamics simulations. We then provide a description of the manner in which phosphorylation at Ser16 modulates the activity of the protein by increasing the sizes of the populations of its excited states. These results demonstrate that the approach that we describe provides a detailed characterization of the different states of phospholamban that determine the function and regulation of this membrane protein. We anticipate that the knowledge of conformational ensembles enable the design of new dominant negative mutants of phospholamban by modulating the relative populations of its conformational substates.

Original languageEnglish
JournalBiochemistry
Volume52
Issue number38
Pages (from-to)6684-94
Number of pages11
ISSN0006-2960
DOIs
Publication statusPublished - 24 Sep 2013
Externally publishedYes

    Research areas

  • Amino Acid Sequence, Calcium-Binding Proteins/chemistry, Humans, Models, Molecular, Molecular Dynamics Simulation, Nuclear Magnetic Resonance, Biomolecular/methods, Phosphorylation, Protein Conformation, Serine/metabolism

ID: 329435141