Conformational cycle of human polyamine transporter ATP13A2.
Conformational cycle of human polyamine transporter ATP13A2.
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人多胺转运蛋白ATP13A2的构象周期。
DOI：
10.1038/s41467-023-37741-0
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发表时间：
2023-04-08
影响因子：
16.6
通讯作者：
Liu, Zhongmin
中科院分区：
文献类型：
--
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
多胺动态平衡失调与人类疾病密切相关。ATP13A2在幼年型帕金森病和常染色体隐性遗传性痉挛截瘫78中发生突变，是一种转运蛋白，在平衡溶酶体和胞浆中的多胺浓度方面起着关键作用。在这里，为了更好地了解人类ATP13A2介导的多胺转运，我们使用单粒子冷冻电子显微镜来解析人类ATP13A2在六个中间状态的高分辨率结构，包括P型ATPase的P5亚家族的假定的E2结构。这些结构包括一个几乎完整的构象循环，跨越多胺运输过程并捕获沿跨膜区分布的多个底物结合部位，暗示了潜在的多胺运输途径。高分辨结构、生化分析和分子动力学模拟的结合使我们能够更好地了解hATP13A2如何运输多胺的结构基础，为ATP13A2相关疾病提供了一个机制框架。ATP13A2是一种溶酶体多胺转运蛋白，在包括青少年帕金森氏病在内的多种疾病中发生突变。在这里，作者报告了人类ATP13A2在六个不同中间状态的结构，说明了其大部分构象周期。
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. 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.
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影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
人P5B型ATP酶ATP13A2的冷冻电镜结构和转运机制
影响因子：
33.5
作者：
Chen X;Zhou M;Zhang S;Yin J;Zhang P;Xuan X;Wang P;Liu Z;Zhou B;Yang M
通讯作者：
Yang M
影响因子：
9.9
作者：
Di Fonzo, A.;Chien, H. F.;Bonifati, V.
通讯作者：
Bonifati, V.
影响因子：
1.7
作者：
Lenis, Yasser Y.;Elmetwally, Mohammed A.;Bazer, Fuller W.
通讯作者：
Bazer, Fuller W.