Structures of human pannexin 1 reveal ion pathways and mechanism of gating.
Structures of human pannexin 1 reveal ion pathways and mechanism of gating.
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DOI：
10.1038/s41586-020-2357-y
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发表时间：
2020-08
期刊：
影响因子：
64.8
通讯作者：
Lü W
中科院分区：
文献类型：
--
作者：
Ruan Z;Orozco IJ;Du J;Lü W
Pannexin 1 （PANX1）是一种atp可渗透通道，在血压调节、凋亡细胞清除和人类卵母细胞发育等多种生理功能中发挥重要作用。我们在分辨率高达2.8 Å的七聚体组装中提出了几种人类PANX1结构，包括载子状态，caspase 7-cleaved状态，cbx结合状态。我们阐述了一种新的门控机制，涉及使用两个离子传导途径。在正常的细胞状态下，宽主孔的胞内入口被c端尾部物理阻塞。小的阴离子通过细胞内狭窄的通道传导。这些通道连接到主孔，并由n端螺旋和第一个跨膜螺旋之间的长连接物进行门控。在细胞凋亡过程中，c端尾部被caspase切割，允许ATP通过主孔释放。我们确定了W74在细胞外入口包含的一个卡贝诺洛酮（CBX）结合位点，以及CBX作为通道阻滞剂的作用。我们使用糖基化缺陷突变体N255A捕获了间隙连接样结构。我们的研究为理解通道门控和PANX1及相关大孔通道抑制的分子机制提供了坚实的基础。
Pannexin 1 (PANX1) is an ATP-permeable channel crucially involved in a variety of physiological functions such as blood pressure regulation, apoptotic cell clearance, and human oocyte development. We present several human PANX1 structures in a heptameric assembly at resolutions up to 2.8 Å, including an apo state, a caspase 7-cleaved state, a CBX-bound state. We elaborate a novel gating mechanism that involves the use of two ion-conducting pathways. Under normal cellular conditions, the intracellular entry of the wide main pore is physically plugged by the C-terminal tail. Small anions are conducted through narrow tunnels in the intracellular domain. These tunnels connect to the main pore and are gated by a long linker between the N-terminal helix and the first transmembrane helix. During apoptosis, the C-terminal tail is cleaved by caspase, allowing the release of ATP through the main pore. We identified a carbenoxolone (CBX) binding site embraced by W74 in the extracellular entrance and also a role for CBX as a channel blocker. We captured a gap junction-like structure using a glycosylation-deficient mutant, N255A. Our studies provided a solid foundation for understanding the molecular mechanisms underlying the channel gating and inhibition of PANX1 and related large-pore channels.
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DOI：
10.1107/s2059798318009324
发表时间：
2018-09-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Klaholz BP;Moriarty NW;Poon BK;Sobolev OV;Terwilliger TC;Adams PD;Urzhumtsev A
通讯作者：
Urzhumtsev A
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
影响因子：
3.6
作者：
Beckmann, Anja;Grissmer, Alexander;Meier, Carola
通讯作者：
Meier, Carola
影响因子：
5.5
作者：
Hess, Berk
通讯作者：
Hess, Berk
影响因子：
14.9
作者：
Drozdetskiy A;Cole C;Procter J;Barton GJ
通讯作者：
Barton GJ