Conformational cycle of human polyamine transporter ATP13A2

作者：Mu, Jianqiang; Xue, Chenyang; Fu, Lei; Yu, Zongjun; Nie, Minhan; Wu, Mengqi; Chen, Xinmeng; Liu, Kun; Bu, Ruiqian; Huang, Ying; Yang, Baisheng; Han, Jianming; Jiang, Qianru; Chan, Kevin C.; Zhou, Ruhong; Li, Huilin; Huang, Ancheng; Wang, Yong^*; Liu, Zhongmin^*

来源：Nature Communications, 2023, 14(1): 1978.

DOI：10.1038/s41467-023-37741-0

• LYSOSOMAL DYSFUNCTION
• ALPHA-SYNUCLEIN
• MUTATIONS
• LEADS
• PARKINSONISM
• DEFICIENCY
• PREDICTION
• MOLECULES
• DYNAMICS
• LIPIDS

ATP13A2 is a lysosomal polyamine transporter, mutated in several diseases including juvenile-onset Parkinson's disease. Here, the authors report structures of human ATP13A2 in six distinct intermediate states, illustrating most of its conformational cycle. @@@ 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.

• 单位
  中山大学; 浙江大学