Structure and transport mechanism of the human calcium pump SPCA1

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,...

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Bibliographic Details
Published in:Cell research 2023-07, Vol.33 (7), p.533-545
Main Authors: Wu, Mengqi, Wu, Cang, Song, Tiefeng, Pan, Kewu, Wang, Yong, Liu, Zhongmin
Format: Article
Language:English
Subjects:
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631/337
631/535/1258/1259
Adenosine Triphosphatases - metabolism
Binding sites
Biomedical and Life Sciences
Breast cancer
Ca2+-transporting ATPase
Calcium - metabolism
Calcium homeostasis
Calcium influx
Calcium ions
Calcium transport
Calcium-binding protein
Calcium-Transporting ATPases - metabolism
Cell Biology
Cryoelectron Microscopy
Electron microscopy
Endoplasmic reticulum
Helices
Homeostasis
Humans
Life Sciences
Microscopy
Molecular dynamics
Phosphorylation
Proteins
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Summary: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.
ISSN:1748-7838
1001-0602
1748-7838
DOI:10.1038/s41422-023-00827-x