7bt2
Crystal structure of the SERCA2a in the E2.ATP stateCrystal structure of the SERCA2a in the E2.ATP state
Structural highlights
Disease[AT2A2_HUMAN] Darier disease;Acrokeratosis verruciformis of Hopf. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Function[AT2A2_HUMAN] This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen. Isoform 2 is involved in the regulation of the contraction/relaxation cycle (PubMed:16402920). 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 (By similarity).[UniProtKB:O55143][1] Publication Abstract from PubMedUnder physiological conditions, most Ca(2+)-ATPase (SERCA) molecules bind ATP before binding the Ca(2+) transported. SERCA has a high affinity for ATP even in the absence of Ca(2+), and ATP accelerates Ca(2+) binding at pH values lower than 7, where SERCA is in the E2 state with low-affinity Ca(2+)-binding sites. Here we describe the crystal structure of SERCA2a, the isoform predominant in cardiac muscle, in the E2.ATP state at 3.0-A resolution. In the crystal structure, the arrangement of the cytoplasmic domains is distinctly different from that in canonical E2. The A-domain now takes an E1 position, and the N-domain occupies exactly the same position as that in the E1.ATP.2Ca(2+) state relative to the P-domain. As a result, ATP is properly delivered to the phosphorylation site. Yet phosphoryl transfer never takes place without the filling of the two transmembrane Ca(2+)-binding sites. The present crystal structure explains what ATP binding itself does to SERCA and how nonproductive phosphorylation is prevented in E2. What ATP binding does to the Ca(2+) pump and how nonproductive phosphoryl transfer is prevented in the absence of Ca(2).,Kabashima Y, Ogawa H, Nakajima R, Toyoshima C Proc Natl Acad Sci U S A. 2020 Jul 16. pii: 2006027117. doi:, 10.1073/pnas.2006027117. PMID:32675243[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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