Title: 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

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.

Link:  https://doi.org/10.1038/s41467-023-37741-0