PT - JOURNAL ARTICLE AU - Aljona Sitsel AU - Joren De Raeymaecker AU - Nikolaj Düring Drachmann AU - Rita Derua AU - Susanne Smaardijk AU - Jacob Lauwring Andersen AU - Ilse Vandecaetsbeek AU - Jialin Chen AU - Marc De Maeyer AU - Etienne Waelkens AU - Claus Olesen AU - Peter Vangheluwe AU - Poul Nissen TI - Structures of the heart specific SERCA2a Ca<sup>2+</sup>-ATPase AID - 10.1101/344911 DP - 2018 Jan 01 TA - bioRxiv PG - 344911 4099 - http://biorxiv.org/content/early/2018/06/12/344911.short 4100 - http://biorxiv.org/content/early/2018/06/12/344911.full 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