7yah

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CryoEM structure of SPCA1a in E1-Ca-AMPPCP state subclass 2CryoEM structure of SPCA1a in E1-Ca-AMPPCP state subclass 2

Structural highlights

7yah is a 2 chain structure with sequence from Homo sapiens and Vicugna pacos. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.12Å
Ligands:,
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][1] [2] [3] [4] [5] [6] [7] [8]

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[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Hu Z, Bonifas JM, Beech J, Bench G, Shigihara T, Ogawa H, Ikeda S, Mauro T, Epstein EH Jr. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000 Jan;24(1):61-5. PMID:10615129 doi:10.1038/71701
  2. ↑ Fairclough RJ, Dode L, Vanoevelen J, Andersen JP, Missiaen L, Raeymaekers L, Wuytack F, Hovnanian A. Effect of Hailey-Hailey Disease mutations on the function of a new variant of human secretory pathway Ca2+/Mn2+-ATPase (hSPCA1). J Biol Chem. 2003 Jul 4;278(27):24721-30. PMID:12707275 doi:10.1074/jbc.M300509200
  3. ↑ Behne MJ, Tu CL, Aronchik I, Epstein E, Bench G, Bikle DD, Pozzan T, Mauro TM. Human keratinocyte ATP2C1 localizes to the Golgi and controls Golgi Ca2+ stores. J Invest Dermatol. 2003 Oct;121(4):688-94. PMID:14632183 doi:10.1046/j.1523-1747.2003.12528.x
  4. ↑ Dode L, Andersen JP, Raeymaekers L, Missiaen L, Vilsen B, Wuytack F. Functional comparison between secretory pathway Ca2+/Mn2+-ATPase (SPCA) 1 and sarcoplasmic reticulum Ca2+-ATPase (SERCA) 1 isoforms by steady-state and transient kinetic analyses. J Biol Chem. 2005 Nov 25;280(47):39124-34. PMID:16192278 doi:10.1074/jbc.M506181200
  5. ↑ Dode L, Andersen JP, Vanoevelen J, Raeymaekers L, Missiaen L, Vilsen B, Wuytack F. Dissection of the functional differences between human secretory pathway Ca2+/Mn2+-ATPase (SPCA) 1 and 2 isoenzymes by steady-state and transient kinetic analyses. J Biol Chem. 2006 Feb 10;281(6):3182-9. PMID:16332677 doi:10.1074/jbc.M511547200
  6. ↑ Lissandron V, Podini P, Pizzo P, Pozzan T. Unique characteristics of Ca2+ homeostasis of the trans-Golgi compartment. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9198-203. PMID:20439740 doi:10.1073/pnas.1004702107
  7. ↑ Mukhopadhyay S, Linstedt AD. Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn2+ efflux and protects against toxicity. Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):858-63. PMID:21187401 doi:10.1073/pnas.1013642108
  8. ↑ Chen J, Smaardijk S, Mattelaer CA, Pamula F, Vandecaetsbeek I, Vanoevelen J, Wuytack F, Lescrinier E, Eggermont J, Vangheluwe P. An N-terminal Ca(2+)-binding motif regulates the secretory pathway Ca(2+)/Mn(2+)-transport ATPase SPCA1. J Biol Chem. 2019 May 10;294(19):7878-7891. PMID:30923126 doi:10.1074/jbc.RA118.006250
  9. ↑ Chen Z, Watanabe S, Hashida H, Inoue M, Daigaku Y, Kikkawa M, Inaba K. Cryo-EM structures of human SPCA1a reveal the mechanism of Ca(2+)/Mn(2+) transport into the Golgi apparatus. Sci Adv. 2023 Mar 3;9(9):eadd9742. PMID:36867705 doi:10.1126/sciadv.add9742

7yah, resolution 3.12Å

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