Structures of the heart specific SERCA2a Ca 2+ -ATPase

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DOI

  • Aljona Sitsel
  • Joren De Raeymaecker, Instituut voor Kern- en Stralingsfysica
  • ,
  • Nikolaj Düring Drachmann, Center for Membrane Proteins in Cells and Disease – PUMPkin
  • ,
  • Rita Derua, Instituut voor Kern- en Stralingsfysica
  • ,
  • Susanne Smaardijk, Instituut voor Kern- en Stralingsfysica
  • ,
  • Jacob Lauwring Andersen, Center for Membrane Proteins in Cells and Disease – PUMPkin
  • ,
  • Ilse Vandecaetsbeek, Department of Cellular and Molecular Medicine, Instituut voor Kern- en Stralingsfysica
  • ,
  • Jialin Chen, Instituut voor Kern- en Stralingsfysica
  • ,
  • Marc De Maeyer, Instituut voor Kern- en Stralingsfysica
  • ,
  • Etienne Waelkens, Instituut voor Kern- en Stralingsfysica
  • ,
  • Claus Olesen
  • Peter Vangheluwe, Instituut voor Kern- en Stralingsfysica
  • ,
  • Poul Nissen

The sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) performs active reuptake of cytoplasmic Ca 2+ and is a major regulator of cardiac muscle contractility. Dysfunction or dysregulation of SERCA2a is associated with heart failure, while restoring its function is considered as a therapeutic strategy to restore cardiac performance. However, its structure has not yet been determined. Based on native, active protein purified from pig ventricular muscle, we present the first crystal structures of SERCA2a, determined in the CPA-stabilized E2 -ALF - 4 form (3.3 Å) and the Ca 2+ -occluded [Ca 2 ]E1-AMPPCP form (4.0 Å). The structures are similar to the skeletal muscle isoform SERCA1a pointing to a conserved mechanism. We seek to explain the kinetic differences between SERCA1a and SERCA2a. We find that several isoform-specific residues are acceptor sites for post-translational modifications. In addition, molecular dynamics simulations predict that isoform-specific residues support distinct intramolecular interactions in SERCA2a and SERCA1a. Our experimental observations further indicate that isoform-specific intramolecular interactions are functionally relevant, and may explain the kinetic differences between SERCA2a and SERCA1a.

Original languageEnglish
Article numbere100020
JournalEMBO Journal
Volume38
Issue5
ISSN0261-4189
DOIs
Publication statusPublished - Mar 2019

    Research areas

  • Ca transport, Ca -ATPase, crystal structure, heart failure, molecular dynamics

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