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Quaternary structure independent folding of voltage-gated ion channel pore domain subunits
Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date : 2022-06-02 , DOI: 10.1038/s41594-022-00775-x
Cristina Arrigoni 1, 2 , Marco Lolicato 1, 2 , David Shaya 1 , Ahmed Rohaim 1 , Felix Findeisen 1 , Lam-Kiu Fong 1, 3 , Claire M Colleran 1 , Pawel Dominik 4 , Sangwoo S Kim 4 , Jonathan P Schuermann 5 , William F DeGrado 1, 3 , Michael Grabe 1, 3 , Anthony A Kossiakoff 4 , Daniel L Minor 1, 6, 7, 8, 9
Affiliation  

Every voltage-gated ion channel (VGIC) has a pore domain (PD) made from four subunits, each comprising an antiparallel transmembrane helix pair bridged by a loop. The extent to which PD subunit structure requires quaternary interactions is unclear. Here, we present crystal structures of a set of bacterial voltage-gated sodium channel (BacNaV) ‘pore only’ proteins that reveal a surprising collection of non-canonical quaternary arrangements in which the PD tertiary structure is maintained. This context-independent structural robustness, supported by molecular dynamics simulations, indicates that VGIC-PD tertiary structure is independent of quaternary interactions. This fold occurs throughout the VGIC superfamily and in diverse transmembrane and soluble proteins. Strikingly, characterization of PD subunit-binding Fabs indicates that non-canonical quaternary PD conformations can occur in full-length VGICs. Together, our data demonstrate that the VGIC-PD is an autonomously folded unit. This property has implications for VGIC biogenesis, understanding functional states, de novo channel design, and VGIC structural origins.



中文翻译:

电压门控离子通道孔域亚基的四级结构独立折叠

每个电压门控离子通道 (VGIC) 都有一个由四个亚基组成的孔域 (PD),每个亚基都包含一个反平行跨膜螺旋对,由一个环桥接。PD 亚基结构需要四级相互作用的程度尚不清楚。在这里,我们展示了一组细菌电压门控钠通道 (BacNa V) “仅孔隙”蛋白质揭示了令人惊讶的非规范四级排列集合,其中保留了 PD 三级结构。这种由分子动力学模拟支持的上下文无关的结构稳健性表明 VGIC-PD 三级结构独立于四级相互作用。这种折叠发生在整个 VGIC 超家族和不同的跨膜蛋白和可溶性蛋白中。引人注目的是,PD 亚基结合 Fab 的表征表明非规范的四元 PD 构象可以出现在全长 VGIC 中。总之,我们的数据表明 VGIC-PD 是一个自主折叠的单元。此属性对 VGIC 生物发生、理解功能状态、从头通道设计和 VGIC 结构起源有影响。

更新日期:2022-06-02
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