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-Structure paper
タイトル | Conformational cycle of human polyamine transporter ATP13A2. |
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ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 1978, Year 2023 |
掲載日 | 2023年4月8日 |
著者 | Jianqiang Mu / Chenyang Xue / Lei Fu / Zongjun Yu / Minhan Nie / Mengqi Wu / Xinmeng Chen / Kun Liu / Ruiqian Bu / Ying Huang / Baisheng Yang / Jianming Han / Qianru Jiang / Kevin C Chan / Ruhong Zhou / Huilin Li / Ancheng Huang / Yong Wang / Zhongmin Liu / |
PubMed 要旨 | 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 ...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. |
リンク | Nat Commun / PubMed:37031211 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.2 - 5.65 Å |
構造データ | EMDB-35384, PDB-8iek: EMDB-35385, PDB-8iel: EMDB-35386, PDB-8iem: EMDB-35387, PDB-8ien: EMDB-35388, PDB-8ieo: EMDB-35391, PDB-8ier: EMDB-35392, PDB-8ies: |
化合物 | ChemComp-ATP: ChemComp-MG: ChemComp-SPM: ChemComp-BEF: ChemComp-ALF: ChemComp-ADP: |
由来 |
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キーワード | PROTEIN TRANSPORT / Cryo-EM structure of ATP13A2 in the E1-ATP state; Membran protein / Cryo-EM structure of ATP13A2 in the E1-like state / membrane protein / Cryo-EM structure of ATP13A2 in the E2P state; Membran protein / TRANSPORT PROTEIN / Cryo-EM structure of ATP13A2 in the E2-Pi state / Cryo-EM structure of ATP13A2 in the nominal E1P state; Membrane protein / Cryo-EM structure of ATP13A2 in the putative of E2 state; Membrane protein / Cryo-EM structure of ATP13A2 in the E1P-ADP state; Membrane protein |