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Structure of Ca2+ ATPase
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 (ER) Ca(2+)-ATPase 2b (SERCA2b) is a ubiquitously expressed membrane protein that facilitates Ca(2+) uptake from the cytosol to the ER. SERCA2b includes a characteristic 11(th) transmembrane helix (TM11) followed by a luminal tail, but the structural basis of SERCA regulation by these C-terminal segments remains unclear. Here, we determined the crystal structures of SERCA2b and its C-terminal splicing variant SERCA2a, both in the E1-2Ca(2+)-adenylyl methylenediphosphonate (AMPPCP) state. Despite discrepancies with the previously reported structural model of SERCA2b, TM11 was found to be located adjacent to TM10 and to interact weakly with a part of the L8/9 loop and the N-terminal end of TM10, thereby inhibiting the SERCA2b catalytic cycle. Accordingly, mutational disruption of the interactions between TM11 and its neighboring residues caused SERCA2b to display SERCA2a-like ATPase activity. We propose that TM11 serves as a key modulator of SERCA2b activity by fine-tuning the intramolecular interactions with other transmembrane regions. Structural Basis of Sarco/Endoplasmic Reticulum Ca(2+)-ATPase 2b Regulation via Transmembrane Helix Interplay.,Inoue M, Sakuta N, Watanabe S, Zhang Y, Yoshikaie K, Tanaka Y, Ushioda R, Kato Y, Takagi J, Tsukazaki T, Nagata K, Inaba K Cell Rep. 2019 Apr 23;27(4):1221-1230.e3. doi: 10.1016/j.celrep.2019.03.106. PMID:31018135[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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