Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
Mol Cell. 2021 Nov 18;81(22):4650-4662.e4. doi: 10.1016/j.molcel.2021.10.002. Epub 2021 Oct 28.
Mutations in ATP13A2, also known as PARK9, cause a rare monogenic form of juvenile-onset Parkinson's disease named Kufor-Rakeb syndrome and other neurodegenerative diseases. ATP13A2 encodes a neuroprotective P5B P-type ATPase highly enriched in the brain that mediates selective import of spermine ions from lysosomes into the cytosol via an unknown mechanism. Here we present three structures of human ATP13A2 bound to an ATP analog or to spermine in the presence of phosphomimetics determined by cryoelectron microscopy. ATP13A2 autophosphorylation opens a lysosome luminal gate to reveal a narrow lumen access channel that holds a spermine ion in its entrance. ATP13A2's architecture suggests physical principles underlying selective polyamine transport and anticipates a "pump-channel" intermediate that could function as a counter-cation conduit to facilitate lysosome acidification. Our findings establish a firm foundation to understand ATP13A2 mutations associated with disease and bring us closer to realizing ATP13A2's potential in neuroprotective therapy.
ATP13A2 突变，也称为 PARK9，导致一种罕见的单基因形式的青少年起病帕金森病，称为 Kufor-Rakeb 综合征和其他神经退行性疾病。ATP13A2 编码一种神经保护 P5B P 型 ATP 酶，在大脑中高度丰富，通过未知机制介导从溶酶体向细胞质中选择性导入精胺离子。在这里，我们通过冷冻电镜显微镜确定了三种与人 ATP13A2 结合的 ATP 类似物或在磷酸模拟物存在下与精胺结合的结构。ATP13A2 的自动磷酸化打开了溶酶体腔门，揭示了一个狭窄的腔入口通道，在入口处保留了一个精胺离子。ATP13A2 的结构表明了选择性多胺运输的物理原理，并预示着“泵-通道”中间物可能作为抗衡离子导管，促进溶酶体酸化。我们的发现为理解与疾病相关的 ATP13A2 突变奠定了坚实的基础，并使我们更接近于实现 ATP13A2 在神经保护治疗中的潜力。
