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-Structure paper
タイトル | Structural mechanisms for gating and ion selectivity of the human polyamine transporter ATP13A2. |
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ジャーナル・号・ページ | Mol Cell, Vol. 81, Issue 22, Page 4650-44662.e4, Year 2021 |
掲載日 | 2021年11月18日 |
著者 | Jordan Tillinghast / Sydney Drury / Darren Bowser / Alana Benn / Kenneth Pak Kin Lee / |
PubMed 要旨 | 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 ...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. |
リンク | Mol Cell / PubMed:34715014 |
手法 | EM (単粒子) |
解像度 | 2.7 - 3.0 Å |
構造データ | EMDB-23683, PDB-7m5v: EMDB-23684, PDB-7m5x: EMDB-23685, PDB-7m5y: |
化合物 | ChemComp-MG: ChemComp-1DO: ChemComp-LMT: ChemComp-Y01: ChemComp-D10: ChemComp-D12: ChemComp-NAG: ChemComp-ANP: ChemComp-EUJ: ChemComp-HOH: ChemComp-BEF: ChemComp-CLR: ChemComp-C14: ChemComp-SPK: ChemComp-MF4: |
由来 |
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キーワード | TRANSPORT PROTEIN / ion transport occluded state / MEMBRANE PROTEIN / ion transport inhibited state |