6hxb
SERCA2a from pig heart
Structural highlights
Function[AT2A2_PIG] This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. Isoform SERCA2A is involved in the regulation of the contraction/relaxation cycle. Acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with TMEM64 which is critical for the TNFSF11-induced CREB1 activation and mitochondrial ROS generation necessary for proper osteoclast generation. Association between TMEM64 and SERCA2 in the ER leads to cytosolic Ca (2+) spiking for activation of NFATC1 and production of mitochondrial ROS, thereby triggering Ca (2+) signaling cascades that promote osteoclast differentiation and activation.[UniProtKB:O55143] Publication Abstract from PubMedThe 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-AlF4- form (3.3 A) and the Ca(2+)-occluded [Ca2]E1-AMPPCP form (4.0 A). 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. Structures of the heart specific SERCA2a Ca(2+)-ATPase.,Sitsel A, De Raeymaecker J, Drachmann ND, Derua R, Smaardijk S, Andersen JL, Vandecaetsbeek I, Chen J, De Maeyer M, Waelkens E, Olesen C, Vangheluwe P, Nissen P EMBO J. 2019 Feb 18. pii: embj.2018100020. doi: 10.15252/embj.2018100020. PMID:30777856[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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