Cryo-EM structure of an active bacterial TIR-STING filament complex.
Cryo-EM structure of an active bacterial TIR-STING filament complex.
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DOI：
10.1038/s41586-022-04999-1
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发表时间：
2022-08
期刊：
影响因子：
64.8
通讯作者：
Kranzusch, Philip J.
中科院分区：
文献类型：
--
作者：
Morehouse, Benjamin R.;Yip, Matthew C. J.;Keszei, Alexander F. A.;McNamara-Bordewick, Nora K.;Shao, Sichen;Kranzusch, Philip J.
干扰素基因刺激因子（STING）是一种抗病毒信号蛋白，在动物的先天免疫和原核生物的噬菌体防御中广泛保守。STING的激活需要其通过环状二核苷酸的结合组装成寡聚丝结构，但STING丝组装和延伸的分子基础仍然未知。在这里，我们使用低温电子显微镜，以确定结构的活性Toll/白细胞介素-1受体（TIR）-STING丝复合物从鞘氨醇杆菌屎环状寡核苷酸为基础的抗噬菌体信号系统（CBASS）防御操纵子。细菌TIR-STING丝形成由STING界面驱动，STING界面在同源环二核苷酸信号c-di-GMP的高亲和力识别时暴露。重复的二聚STING单元通过表面界面横向头对头堆叠，这对于哺乳动物中的人STING四聚体形成和下游免疫信号传导也是必需的。活性细菌TIR-STING结构揭示了进一步的交叉细丝接触，其支撑细丝基部处的相关TIR NAD酶效应结构域的组装和协调包装以驱动NAD+水解。STING界面和交叉细丝接触对于体内细胞生长停滞是必不可少的，并且揭示了逐步激活机制，其中STING细丝组装是后续效应物激活所必需的。我们的研究结果定义了原核抗病毒信号传导中STING丝形成的结构基础。通过对细菌STING激活的结构分析，确定了STING丝形成和TIR效应结构域在抗噬菌体信号传导中激活的分子基础。
Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes. Activation of STING requires its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide, but the molecular basis of STING filament assembly and extension remains unknown. Here we use cryogenic electron microscopy to determine the structure of the active Toll/interleukin-1 receptor (TIR)–STING filament complex from a Sphingobacterium faecium cyclic-oligonucleotide-based antiphage signalling system (CBASS) defence operon. Bacterial TIR–STING filament formation is driven by STING interfaces that become exposed on high-affinity recognition of the cognate cyclic dinucleotide signal c-di-GMP. Repeating dimeric STING units stack laterally head-to-head through surface interfaces, which are also essential for human STING tetramer formation and downstream immune signalling in mammals. The active bacterial TIR–STING structure reveals further cross-filament contacts that brace the assembly and coordinate packing of the associated TIR NADase effector domains at the base of the filament to drive NAD+ hydrolysis. STING interface and cross-filament contacts are essential for cell growth arrest in vivo and reveal a stepwise mechanism of activation whereby STING filament assembly is required for subsequent effector activation. Our results define the structural basis of STING filament formation in prokaryotic antiviral signalling. Through structural analysis of the activation of bacterial STING, the molecular basis of STING filament formation and TIR effector domain activation in antiphage signalling is defined.
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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：
48
作者：
Punjani, Ali;Rubinstein, John L.;Brubaker, Marcus A.
通讯作者：
Brubaker, Marcus A.
影响因子：
64.8
作者：
通讯作者：
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DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC