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Structures of the heart specific SERCA 2a Ca 2+ ‐ ATP ase
Author(s) -
Sitsel Aljona,
De Raeymaecker Joren,
Drachmann Nikolaj Düring,
Derua Rita,
Smaardijk Susanne,
Andersen Jacob Lauwring,
Vandecaetsbeek Ilse,
Chen Jialin,
De Maeyer Marc,
Waelkens Etienne,
Olesen Claus,
Vangheluwe Peter,
Nissen Poul
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100020
Subject(s) - biology , serca , adenosine triphosphate , biochemistry , microbiology and biotechnology , enzyme , atpase
The sarcoplasmic/endoplasmic reticulum Ca 2+ ‐ ATP ase 2a ( SERCA 2a) performs active reuptake of cytoplasmic Ca 2+ and is a major regulator of cardiac muscle contractility. Dysfunction or dysregulation of SERCA 2a 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 SERCA 2a, 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 SERCA 1a pointing to a conserved mechanism. We seek to explain the kinetic differences between SERCA 1a and SERCA 2a. 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 SERCA 2a and SERCA 1a. Our experimental observations further indicate that isoform‐specific intramolecular interactions are functionally relevant, and may explain the kinetic differences between SERCA 2a and SERCA 1a.