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Volume 33, No 7, Jul 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 7, July 2023: 533-545   |  Open Access

ORIGINAL ARTICLES

Structure and transport mechanism of the human calcium pump SPCA1

Mengqi Wu1,† , Cang Wu1,† , Tiefeng Song2,† , Kewu Pan3 , Yong Wang2,4,* , Zhongmin Liu1,*

1Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China
2College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
3School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
4The Provincial International Science and Technology Cooperation Base on Engineering Biology, International Campus of Zhejiang University, Haining, Zhejiang, China
These authors contributed equally: Mengqi Wu, Cang Wu, Tiefeng Song
Correspondence: Yong Wang(yongwang_isb@zju.edu.cn)Zhongmin Liu(liuzm@sustech.edu.cn)

Secretory-pathway Ca2+-ATPases (SPCAs) play critical roles in maintaining Ca2+ homeostasis, but the exact mechanism of SPCAs-mediated Ca2+ 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 Ca2+ 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 Ca2+-binding site induced by the separation of transmembrane helices 4L and 6, unveiling a distinct Ca2+ release mechanism. Particularly, we determined a structure of the long-sought CaE2P state of P-type IIA ATPases, providing valuable insights into the Ca2+ transport cycle. Together, these findings enhance our understanding of Ca2+ transport by hSPCA1 and broaden our knowledge of P-type ATPases.


https://doi.org/10.1038/s41422-023-00827-x

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