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Nature communications
04 08, 2023;14 (1): 1978.

Conformational cycle of human polyamine transporter ATP13A2.

Jianqiang Mu, Chenyang Xue, Lei Fu, Zongjun Yu, Minhan Nie, Mengqi Wu, Xinmeng Chen, Kun Liu, Ruiqian Bu, Ying Huang, Baisheng Yang, Jianming Han, Qianru Jiang, Kevin C Chan, Ruhong Zhou, Huilin Li, Ancheng Huang, Yong Wang, Zhongmin Liu
Author Information
  1. Jianqiang Mu: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.
  2. Chenyang Xue: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China. ORCID
  3. Lei Fu: Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, 310027, Hangzhou, China.
  4. Zongjun Yu: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China. ORCID
  5. Minhan Nie: School of Pharmaceutical Sciences, Sun Yat-sen University, No.132 Wai Huan Dong Lu, Guangzhou Higher Education Mega Center, 510006, Guangzhou, China.
  6. Mengqi Wu: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.
  7. Xinmeng Chen: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.
  8. Kun Liu: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.
  9. Ruiqian Bu: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.
  10. Ying Huang: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.
  11. Baisheng Yang: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.
  12. Jianming Han: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.
  13. Qianru Jiang: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.
  14. Kevin C Chan: Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, 310027, Hangzhou, China. ORCID
  15. Ruhong Zhou: Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, 310027, Hangzhou, China. ORCID
  16. Huilin Li: School of Pharmaceutical Sciences, Sun Yat-sen University, No.132 Wai Huan Dong Lu, Guangzhou Higher Education Mega Center, 510006, Guangzhou, China.
  17. Ancheng Huang: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China. ORCID
  18. Yong Wang: Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, 310027, Hangzhou, China. yongwang_isb@zju.edu.cn. ORCID
  19. Zhongmin Liu: Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China. liuzm@sustech.edu.cn. ORCID
PMID: 37031211 DOI: 10.1038/s41467-023-37741-0

Abstract

Dysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2, which is mutated in juvenile-onset Parkinson's disease and autosomal recessive spastic paraplegia 78, is a transporter with a critical role in balancing the polyamine concentration between the lysosome and the cytosol. Here, to better understand human ATP13A2-mediated polyamine transport, we use single-particle cryo-electron microscopy to solve high-resolution structures of human ATP13A2 in six intermediate states, including the putative E2 structure for the P5 subfamily of the P-type ATPases. These structures comprise a nearly complete conformational cycle spanning the polyamine transport process and capture multiple substrate binding sites distributed along the transmembrane regions, suggesting a potential polyamine transport pathway. Integration of high-resolution structures, biochemical assays, and molecular dynamics simulations allows us to obtain a better understanding of the structural basis of how hATP13A2 transports polyamines, providing a mechanistic framework for ATP13A2-related diseases.

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MeSH Term

Humans
Polyamines
Proton-Translocating ATPases
Cryoelectron Microscopy
Parkinsonian Disorders
Membrane Transport Proteins

Chemicals

Polyamines
Proton-Translocating ATPases
Membrane Transport Proteins
ATP13A2 protein, human
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 3

Word Cloud

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