7w7u | pdb_00007w7u
The 'Ca2+-unbound' BeF3- of SERCA2b
Structural highlights
DiseaseAT2A2_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. FunctionAT2A2_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 PubMedSarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) pumps Ca(2+) into the endoplasmic reticulum (ER). Herein, we present cryo-electron microscopy (EM) structures of three intermediates of SERCA2b: Ca(2+)-bound phosphorylated (E1P.2Ca(2+)) and Ca(2+)-unbound dephosphorylated (E2.Pi) intermediates and another between the E2P and E2.Pi states. Our cryo-EM analysis demonstrates that the E1P.2Ca(2+) state exists in low abundance and preferentially transitions to an E2P-like structure by releasing Ca(2+) and that the Ca(2+) release gate subsequently undergoes stepwise closure during the dephosphorylation processes. Importantly, each intermediate adopts multiple sub-state structures including those like the next one in the catalytic series, indicating conformational overlap at transition steps, as further substantiated by atomistic molecular dynamic simulations of SERCA2b in a lipid bilayer. The present findings provide insight into how enzymes accelerate catalytic cycles. Multiple sub-state structures of SERCA2b reveal conformational overlap at transition steps during the catalytic cycle.,Zhang Y, Kobayashi C, Cai X, Watanabe S, Tsutsumi A, Kikkawa M, Sugita Y, Inaba K Cell Rep. 2022 Dec 6;41(10):111760. doi: 10.1016/j.celrep.2022.111760. PMID:36476867[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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