Structural basis of RNA recognition and activation by innate immune receptor RIG-I.
Structural basis of RNA recognition and activation by innate immune receptor RIG-I.
复制标题
DOI：
10.1038/nature10537
复制
发表时间：
2011-09-25
期刊：
影响因子：
64.8
通讯作者：
Marcotrigiano, Joseph
中科院分区：
文献类型：
--
作者：
Jiang, Fuguo;Ramanathan, Anand;Miller, Matthew T.;Tang, Guo-Qing;Gale, Michael, Jr.;Patel, Smita S.;Marcotrigiano, Joseph
RIG-I（视黄酸诱导基因- I）是细胞质病原体识别受体，其识别病原体相关分子模式（PAMP）基序以区分病毒和细胞RNA。RIG-I被具有或不具有5′-三磷酸（ppp）的平端双链（ds）RNA、由5′-ppp和聚尿苷序列标记的单链（ss）RNA激活。在与这种PAMP基序结合后，RIG-I启动信号级联，其诱导先天免疫防御和炎性细胞因子以建立抗病毒状态。RIG-I途径受到高度调节，异常信号传导导致细胞凋亡、细胞分化改变、炎症、自身免疫性疾病和癌症。RIG-I的解旋酶和阻遏物结构域（RD）识别dsRNA和5′-ppp RNA，以激活氨基末端的两个CARD来进行信号传导。为了了解解旋酶和RD之间的RNA结合的协同作用以及ATP水解对RIG-I活化的贡献，我们确定了与dsRNA和ATP类似物复合的人RIG-I解旋酶-RD的结构。解旋酶-RD组织成围绕dsRNA的环，将一端加帽，同时利用先前未表征的基序接触两条链以识别dsRNA。小角X射线散射（SAXS），有限的蛋白水解，和差示扫描荧光法（DSF）表明，RIG-I是在一个扩展的和灵活的构象，结合RNA压缩。这些结果提供了解旋酶在dsRNA识别中的作用、RD与解旋酶之间的协同作用、与dsRNA结合的全长RIG-I的组织以及RNA结合后构象变化的证据的详细视图。RIG-I解旋酶-RD结构与dsRNA易位一致，而没有解旋和与RNA的合作结合。该结构对先天免疫产生了前所未有的洞察力，并对生物学的其他领域产生了更广泛的影响，包括RNA干扰和DNA修复，这些领域利用了Dicer和FANCM中的同源解旋酶结构域。
RIG-I (Retinoic acid Inducible Gene - I) is a cytoplasmic pathogen recognition receptor that recognizes pathogen-associated molecular pattern (PAMP) motifs to differentiate between viral and cellular RNAs. RIG-I is activated by blunt-ended double-stranded (ds) RNA with or without a 5′-triphosphate (ppp), single-stranded (ss) RNA marked by 5′-ppp and poly-uridine sequence. Upon binding to such PAMP motifs, RIG-I initiates a signaling cascade that induces innate immune defenses and inflammatory cytokines to establish an antiviral state. The RIG-I pathway is highly regulated and aberrant signaling leads to apoptosis, altered cell differentiation, inflammation, autoimmune diseases, and cancer. The helicase and repressor domain (RD) of RIG-I recognize dsRNA and 5′-ppp RNA to activate the amino-terminal two CAspase Recruitment Domains (CARDs) for signaling. To understand the synergy between helicase and RD for RNA binding and the contribution of ATP hydrolysis to RIG-I activation, we determined the structure of human RIG-I helicase-RD in complex with dsRNA and an ATP-analog. The helicase-RD organizes into a ring around dsRNA, capping one end, while contacting both strands utilizing previously uncharacterized motifs to recognize dsRNA. Small angle X-ray scattering (SAXS), limited proteolysis, and differential scanning fluorimetry (DSF) suggest that RIG-I is in an extended and flexible conformation that compacts upon binding RNA. These results provide a detailed view of the helicase role in dsRNA recognition, the synergy between RD and the helicase for RNA binding, organization of full-length RIG-I bound to dsRNA, and evidence of a conformational change upon RNA binding. The RIG-I helicase-RD structure is consistent with dsRNA translocation without unwinding and cooperative binding to RNA. The structure yields unprecedented insight into innate immunity and has broader impact into other areas of biology, including RNA interference and DNA repair, which utilize homologous helicase domains within Dicer and FANCM.
登录
查看更多内容
影响因子：
14.9
作者：
Lu C;Ranjith-Kumar CT;Hao L;Kao CC;Li P
通讯作者：
Li P
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：
6.1
作者：
Konarev, PV;Volkov, VV;Svergun, DI
通讯作者：
Svergun, DI
影响因子：
64.8
作者：
Meylan, E;Curran, J;Tschopp, R
通讯作者：
Tschopp, R
影响因子：
30.5
作者：
Kawai, T;Takahashi, K;Akira, S
通讯作者：
Akira, S