7yam

CryoEM structure of SPCA1a in E2P state

spinqualitylabelsall models 7yam, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7yam is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.3Å Ligands: BEF, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease AT2C1_HUMAN Hailey-Hailey disease. The disease is caused by variants affecting the gene represented in this entry. Function AT2C1_HUMAN ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway (PubMed:12707275, PubMed:16192278, PubMed:20439740, PubMed:21187401, PubMed:30923126). Within a catalytic cycle, acquires Ca(2+) or Mn(2+) ions on the cytoplasmic side of the membrane and delivers them to the lumenal side. The transfer of ions across the membrane is coupled to ATP hydrolysis and is associated with a transient phosphorylation that shifts the pump conformation from inward-facing to outward-facing state (PubMed:16192278, PubMed:16332677, PubMed:30923126). Plays a primary role in the maintenance of Ca(2+) homeostasis in the trans-Golgi compartment with a functional impact on Golgi and post-Golgi protein sorting as well as a structural impact on cisternae morphology (PubMed:14632183, PubMed:20439740). Responsible for loading the Golgi stores with Ca(2+) ions in keratinocytes, contributing to keratinocyte differentiation and epidermis integrity (PubMed:10615129, PubMed:14632183, PubMed:20439740). Participates in Ca(2+) and Mn(2+) ions uptake into the Golgi store of hippocampal neurons and regulates protein trafficking required for neural polarity (By similarity). May also play a role in the maintenance of Ca(2+) and Mn(2+) homeostasis and signaling in the cytosol while preventing cytotoxicity (PubMed:21187401).[UniProtKB:Q80XR2] Publication Abstract from PubMed Secretory pathway Ca(2+)/Mn(2+) ATPase 1 (SPCA1) actively transports cytosolic Ca(2+) and Mn(2+) into the Golgi lumen, playing a crucial role in cellular calcium and manganese homeostasis. Detrimental mutations of the ATP2C1 gene encoding SPCA1 cause Hailey-Hailey disease. Here, using nanobody/megabody technologies, we determined cryo-electron microscopy structures of human SPCA1a in the ATP and Ca(2+)/Mn(2+)-bound (E1-ATP) state and the metal-free phosphorylated (E2P) state at 3.1- to 3.3-A resolutions. The structures revealed that Ca(2+) and Mn(2+) share the same metal ion-binding pocket with similar but notably different coordination geometries in the transmembrane domain, corresponding to the second Ca(2+)-binding site in sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA). In the E1-ATP to E2P transition, SPCA1a undergoes similar domain rearrangements to those of SERCA. Meanwhile, SPCA1a shows larger conformational and positional flexibility of the second and sixth transmembrane helices, possibly explaining its wider metal ion specificity. These structural findings illuminate the unique mechanisms of SPCA1a-mediated Ca(2+)/Mn(2+) transport. Cryo-EM structures of human SPCA1a reveal the mechanism of Ca(2+)/Mn(2+) transport into the Golgi apparatus.,Chen Z, Watanabe S, Hashida H, Inoue M, Daigaku Y, Kikkawa M, Inaba K Sci Adv. 2023 Mar 3;9(9):eadd9742. doi: 10.1126/sciadv.add9742. Epub 2023 Mar 3. PMID:36867705 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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