Multi-faceted studies the key
Integration of high-resolution structures, biochemical assays, and molecular dynamics simulations provides a framework for understanding the disease mechanism behind SPG78 and related diseases such as juvenile-onset Parkinson’s.
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.
SOURCE: Nat Commun. 2023 Apr 8;14(1):1978. doi: 10.1038/s41467-023-37741-0. PMID: 37031211 © 2023. The Author(s).
Conformational cycle of human polyamine transporter ATP13A2
Jianqiang Mu # 1 , Chenyang Xue # 1 , Lei Fu # 2 , Zongjun Yu 1 , Minhan Nie 3 , Mengqi Wu 1 , Xinmeng Chen 1 , Kun Liu 1 , Ruiqian Bu 1 , Ying Huang 1 , Baisheng Yang 1 , Jianming Han 1 , Qianru Jiang 1 , Kevin C Chan 2 , Ruhong Zhou 2 , Huilin Li 3 4 , Ancheng Huang 1 , Yong Wang 5 6 , Zhongmin Liu 7
1. Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.
2. Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, 310027, Hangzhou, China.
3. School of Pharmaceutical Sciences, Sun Yat-sen University, No.132 Wai Huan Dong Lu, Guangzhou Higher Education Mega Center, 510006, Guangzhou, China.
4. Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, Guangdong, China.
5. Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, 310027, Hangzhou, China. [email protected].
6. The Provincial International Science and Technology Cooperation Base on Engineering Biology, International Campus of Zhejiang University, 314400, Haining, China.
7. Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China.
#. Contributed equally.