6ln5
From Proteopedia
CryoEM structure of SERCA2b T1032stop in E1-2Ca2+-AMPPCP (class1)
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) pumps Ca(2+) from the cytosol into the ER and maintains the cellular calcium homeostasis. Herein, we present cryo-electron microscopy (cryo-EM) structures of human SERCA2b in E12Ca(2+)-adenylyl methylenediphosphonate (AMPPCP) and E2-BeF3 (-) states at 2.9- and 2.8-A resolutions, respectively. The structures revealed that the luminal extension tail (LE) characteristic of SERCA2b runs parallel to the lipid-water boundary near the luminal ends of transmembrane (TM) helices TM10 and TM7 and approaches the luminal loop flanked by TM7 and TM8. While the LE served to stabilize the cytosolic and TM domain arrangement of SERCA2b, deletion of the LE rendered the overall conformation resemble that of SERCA1a and SERCA2a and allowed multiple conformations. Thus, the LE appears to play a critical role in conformational regulation in SERCA2b, which likely explains the different kinetic properties of SERCA2b from those of other isoforms lacking the LE. Cryo-EM structures of SERCA2b reveal the mechanism of regulation by the luminal extension tail.,Zhang Y, Inoue M, Tsutsumi A, Watanabe S, Nishizawa T, Nagata K, Kikkawa M, Inaba K Sci Adv. 2020 Aug 12;6(33):eabb0147. doi: 10.1126/sciadv.abb0147. eCollection, 2020 Aug. PMID:32851169[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
