7e7s
From Proteopedia
WT transporter state1
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 PubMedSarco/endoplasmic reticulum Ca(2+) -ATPase (SERCA) 2b is a ubiquitous SERCA family member that conducts Ca(2+) uptake from the cytosol to the ER. Herein, we present a 3.3 A resolution cryo-electron microscopy (cryo-EM) structure of human SERCA2b in the E1.2Ca(2+) state, revealing a new conformation for Ca(2+) -bound SERCA2b with a much closer arrangement of cytosolic domains than in the previously reported crystal structure of Ca(2+) -bound SERCA1a. Multiple conformations generated by 3D classification of cryo-EM maps reflect the intrinsically dynamic nature of the cytosolic domains in this state. Notably, ATP binding residues of SERCA2b in the E1.2Ca(2+) state are located at similar positions to those in the E1.2Ca(2+) -ATP state; hence, the cryo-EM structure likely represents a preformed state immediately prior to ATP binding. Consistently, a SERCA2b mutant with an interdomain disulfide bridge that locks the closed cytosolic domain arrangement displayed significant autophosphorylation activity in the presence of Ca(2+) . We propose a novel mechanism of ATP binding to SERCA2b. Cryo-EM analysis provides new mechanistic insight into ATP binding to Ca(2+) -ATPase SERCA2b.,Zhang Y, Watanabe S, Tsutsumi A, Kadokura H, Kikkawa M, Inaba K EMBO J. 2021 Oct 1;40(19):e108482. doi: 10.15252/embj.2021108482. Epub 2021 Aug, 30. PMID:34459010[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Inaba, K | Tsutsumi, A | Watanabe, S | Zhang, Y | Calcium | Metal transport
