Chen Xudong, Zhou Mingze, Zhang Sensen, Yin Jian, Zhang Ping, Xuan Xujun, Wang Peiyi, Liu Zhiqiang, Zhou Boda, Yang Maojun
Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China.
Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
Cell Discov. 2021 Nov 2;7(1):106. doi: 10.1038/s41421-021-00334-6.
Polyamines are important polycations that play critical roles in mammalian cells. ATP13A2 belongs to the orphan P5B adenosine triphosphatases (ATPase) family and has been established as a lysosomal polyamine exporter to maintain the normal function of lysosomes and mitochondria. Previous studies have reported that several human neurodegenerative disorders are related to mutations in the ATP13A2 gene. However, the transport mechanism of ATP13A2 in the lysosome remains unclear. Here, we report the cryo-electron microscopy (cryo-EM) structures of three distinct intermediates of the human ATP13A2, revealing key insights into the spermine (SPM) transport cycle in the lysosome. The transmembrane domain serves as a substrate binding site and the C-terminal domain is essential for protein stability and may play a regulatory role. These findings advance our understanding of the polyamine transport mechanism, the lipid-associated regulation, and the disease-associated mutants of ATP13A2.
多胺是重要的聚阳离子，在哺乳动物细胞中发挥关键作用。ATP13A2属于孤儿P5B三磷酸腺苷酶（ATP酶）家族，已被确定为溶酶体多胺转运体，以维持溶酶体和线粒体的正常功能。先前的研究报道，几种人类神经退行性疾病与ATP13A2基因的突变有关。然而，ATP13A2在溶酶体中的转运机制仍不清楚。在这里，我们报告了人类ATP13A2三种不同中间体的冷冻电子显微镜（cryo-EM）结构，揭示了溶酶体中精胺（SPM）转运循环的关键见解。跨膜结构域作为底物结合位点，C末端结构域对蛋白质稳定性至关重要，可能起调节作用。这些发现推进了我们对ATP13A2的多胺转运机制、脂质相关调节以及疾病相关突变体的理解。
