Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720, USA.
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, 60438 Frankfurt am Main, Germany.
Mol Cell. 2021 Nov 18;81(22):4635-4649.e8. doi: 10.1016/j.molcel.2021.08.017. Epub 2021 Oct 28.
Polyamines are small, organic polycations that are ubiquitous and essential to all forms of life. Currently, how polyamines are transported across membranes is not understood. Recent studies have suggested that ATP13A2 and its close homologs, collectively known as P5B-ATPases, are polyamine transporters at endo-/lysosomes. Loss-of-function mutations of ATP13A2 in humans cause hereditary early-onset Parkinson's disease. To understand the polyamine transport mechanism of ATP13A2, we determined high-resolution cryoelectron microscopy (cryo-EM) structures of human ATP13A2 in five distinct conformational intermediates, which together, represent a near-complete transport cycle of ATP13A2. The structural basis of the polyamine specificity was revealed by an endogenous polyamine molecule bound to a narrow, elongated cavity within the transmembrane domain. The structures show an atypical transport path for a water-soluble substrate, in which polyamines may exit within the cytosolic leaflet of the membrane. Our study provides important mechanistic insights into polyamine transport and a framework to understand the functions and mechanisms of P5B-ATPases.
多胺是一类小型有机聚阳离子，普遍存在于所有生命形式中，是其必需物质。目前，人们尚不清楚多胺如何穿过细胞膜进行转运。最近的研究表明，ATP13A2 及其密切同源物（统称为 P5B-ATP 酶）是内体/溶酶体中的多胺转运体。ATP13A2 基因的功能丧失性突变会导致人类遗传性早发性帕金森病。为了了解 ATP13A2 的多胺转运机制，我们利用 cryo-EM 技术解析了人类 ATP13A2 在五个不同构象中间态的高分辨率结构，这些结构共同代表了 ATP13A2 近乎完整的转运循环。通过与跨膜结构域内狭窄、细长的腔室结合的内源性多胺分子，揭示了多胺特异性的结构基础。这些结构显示出一种针对水溶性底物的非典型转运途径，其中多胺可能在膜胞质小叶内排出。本研究为多胺转运提供了重要的机制见解，并为理解 P5B-ATP 酶的功能和机制提供了框架。
