RT Journal Article SR Electronic T1 Structures of the heart specific SERCA2a Ca2+-ATPase JF bioRxiv FD Cold Spring Harbor Laboratory SP 344911 DO 10.1101/344911 A1 Aljona Sitsel A1 Joren De Raeymaecker A1 Nikolaj Düring Drachmann A1 Rita Derua A1 Susanne Smaardijk A1 Jacob Lauwring Andersen A1 Ilse Vandecaetsbeek A1 Jialin Chen A1 Marc De Maeyer A1 Etienne Waelkens A1 Claus Olesen A1 Peter Vangheluwe A1 Poul Nissen YR 2018 UL http://biorxiv.org/content/early/2018/06/12/344911.abstract AB The isoform 2a of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) performs active reuptake of cytoplasmic Ca2+ 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, but its structure was not yet determined. Based on native, active protein purified from pig ventricular muscle, we present the first crystal structures of SERCA2a that were determined in the CPA-stabilized and H+-occluded [H2-3]E2-AlF4 - (3.3 Å) form, arranged as parallel dimers, and the Ca2+-occluded [Ca2]E1-ATP (4.0 Å) form. We compare these new structures to similar forms of the skeletal muscle SERCA1a and address structural, functional and regulatory differences. We show that the isoform specific motifs of SERCA2a allow a distinct regulation by post-translational modifications and affect the dynamic behavior, which may explain specific properties and regulation.Author ContributionsConceptualization, C.O., P.V., P.N.; Methodology, A.S., N.D., I.V., M.D.M., E.W., C.O., P.V., P.N.; Formal analysis, A.S., N.D., J.L.A., R.D., S.S.; Investigation, A.S., N.D., R.D., S.S., J.D.R., I.V., J.C.; Writing – original draft preparation, A.S., P.N., P.V.; Writing – review and editing, A.S., J.L.A., P.N., P.V.; Visualization, A.S. Supervision, C.O., P.V., P.N.; Funding acquisition, A.S., C.O., P.V., P.N.AbbreviationsSERCASarcoplasmic reticulum Ca2+-ATPaseCPACyclopiazonic acidC12E8octaethylene glycol monododecyl ether