8iwr

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hSPCA1 in the CaE1-ATP state

Structural highlights

8iwr 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 3.52Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AT2C1_HUMAN Familial benign chronic pemphigus. 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:16192278, PubMed:30923126, PubMed:21187401, PubMed:12707275, PubMed:20439740). 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:20439740, PubMed:14632183). Responsible for loading the Golgi stores with Ca(2+) ions in keratinocytes, contributing to keratinocyte differentiation and epidermis integrity (PubMed:14632183, PubMed:10615129, 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+)-ATPases (SPCAs) play critical roles in maintaining Ca(2+) homeostasis, but the exact mechanism of SPCAs-mediated Ca(2+) transport remains unclear. Here, we determined six cryo-electron microscopy (cryo-EM) structures of human SPCA1 (hSPCA1) in a series of intermediate states, revealing a near-complete conformational cycle. With the aid of molecular dynamics simulations, these structures offer a clear structural basis for Ca(2+) entry and release in hSPCA1. We found that hSPCA1 undergoes unique conformational changes during ATP binding and phosphorylation compared to other well-studied P-type II ATPases. In addition, we observed a conformational distortion of the Ca(2+)-binding site induced by the separation of transmembrane helices 4L and 6, unveiling a distinct Ca(2+) release mechanism. Particularly, we determined a structure of the long-sought CaE2P state of P-type IIA ATPases, providing valuable insights into the Ca(2+) transport cycle. Together, these findings enhance our understanding of Ca(2+) transport by hSPCA1 and broaden our knowledge of P-type ATPases.

Structure and transport mechanism of the human calcium pump SPCA1.,Wu M, Wu C, Song T, Pan K, Wang Y, Liu Z Cell Res. 2023 Jul;33(7):533-545. doi: 10.1038/s41422-023-00827-x. Epub 2023 May , 31. PMID:37258749^[9]

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

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ Wu M, Wu C, Song T, Pan K, Wang Y, Liu Z. Structure and transport mechanism of the human calcium pump SPCA1. Cell Res. 2023 Jul;33(7):533-545. PMID:37258749 doi:10.1038/s41422-023-00827-x