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 () and Zhongmin Liu ()
Additional contact information
Jianqiang Mu: Southern University of Science and Technology
Chenyang Xue: Southern University of Science and Technology
Lei Fu: Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University
Zongjun Yu: Southern University of Science and Technology
Minhan Nie: Sun Yat-sen University, No.132 Wai Huan Dong Lu, Guangzhou Higher Education Mega Center
Mengqi Wu: Southern University of Science and Technology
Xinmeng Chen: Southern University of Science and Technology
Kun Liu: Southern University of Science and Technology
Ruiqian Bu: Southern University of Science and Technology
Ying Huang: Southern University of Science and Technology
Baisheng Yang: Southern University of Science and Technology
Jianming Han: Southern University of Science and Technology
Qianru Jiang: Southern University of Science and Technology
Kevin C. Chan: Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University
Ruhong Zhou: Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University
Huilin Li: Sun Yat-sen University, No.132 Wai Huan Dong Lu, Guangzhou Higher Education Mega Center
Ancheng Huang: Southern University of Science and Technology
Yong Wang: Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University
Zhongmin Liu: Southern University of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37741-0

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