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首页> 外文期刊>Nature >Structural basis of RNA recognition and activation by innate immune receptor RIG-I
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Structural basis of RNA recognition and activation by innate immune receptor RIG-I

机译：先天性免疫受体RIG-I识别和激活RNA的结构基础

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摘要

Retinoic-acid-inducible gene-I (RIG-I; also known as DDX58) is a cytoplasmic pathogen recognition receptor that recognizes pathogen-associated molecular pattern (P AMP) 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), by single-stranded RNA marked by a 5'-ppp' and by polyuridine sequences2'3. Upon binding to such PAMP motifs, RIG-I initiates a signalling cascade that induces innate immune defences and inflammatory cytokines to establish an antiviral state. The RIG-I pathway is highly regulated and aberrant signalling leads to apoptosis, altered cell differentiation, inflammation, autoimmune diseases and cancer43. The helicase and repressor domains (RD) of RIG-I recognize dsRNA and 5'-ppp RNA to activate the two amino-terminal caspase recruitment domains (CARDs) for signalling. Here, to understand the synergy between the helicase and the 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 analogue. The helicase-RD organizes into a ring around dsRNA, capping one end, while contacting both strands using previously uncharacterized motifs to recognize dsRNA. Small-angle X-ray scattering, limited proteolysis and differential scanning fluorimetry indicate that RIG-I is in an extended and flexible conformation that compacts upon binding RNA. These results provide a detailed view of the role of helicase in dsRNA recognition, the synergy between the RD and the helicase for RNA binding and the organization of full-length RIG-I bound to dsRNA, and provide 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 a broader impact on other areas of biology, including RNA interference and DNA repair, which utilize homologous helicase domains within DICER and FANCM.
机译：维甲酸诱导基因-I（RIG-I；也称为DDX58）是一种细胞质病原体识别受体，可识别与病原体相关的分子模式（P AMP）图案，以区分病毒RNA和细胞RNA。 RIG-1被具有或不具有5'-三磷酸（ppp）的平末端双链（ds）RNA，以5'-ppp'标记的单链RNA和聚尿苷序列2'3激活。结合到这样的PAMP基序后，RIG-1会启动信号传导级联，该信号级联诱导先天免疫防御和炎性细胞因子建立抗病毒状态。 RIG-I途径受到高度调控，异常信号转导导致凋亡，细胞分化改变，炎症，自身免疫性疾病和癌症43。 RIG-1的解旋酶和阻遏域（RD）识别dsRNA和5'-ppp RNA，以激活两个氨基末端caspase募集域（CARD）发出信号。在这里，为了了解解旋酶和RD之间的结合RNA的协同作用，以及ATP水解对RIG-I激活的贡献，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在dsRNA周围组织成一个环，封住一端，同时使用以前未表征的基序接触两条链以识别dsRNA。小角度X射线散射，有限的蛋白水解和差示扫描荧光法表明RIG-I处于扩展且灵活的构象，可在结合RNA时紧缩。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（用于结合RNA）以及与dsRNA结合的全长RIG-I的组织的详细视图，并提供了RNA结合时构象变化的证据。 RIG-I解旋酶-RD结构与dsRNA易位一致，而不会解链和与RNA协同结合。该结构对先天免疫产生了空前的洞察力，并且对其他生物学领域（包括RNA干扰和DNA修复）产生了更广泛的影响，这些领域利用了DICER和FANCM中的同源解旋酶结构域。

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  • 来源
    《Nature》 |2011年第7373期|p.423-427|共5页
  • 作者

    Fuguo Jiang; Anand Ramanathan; Matthew T. Miller; Guo-Qing Tang; Michael Gale Jr; Smita S. Patel; Joseph Marcotrigiano;

  • 作者单位

    Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, 679 Hoes Lane West, Piscataway, New Jersey 08854, USA;

    Department of Biochemistry, UMDNJ-RWJ Medical School, 675 Hoes Lane West, Piscataway, New Jersey 08854, USA;

    Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, 679 Hoes Lane West, Piscataway, New Jersey 08854, USA;

    Department of Biochemistry, UMDNJ-RWJ Medical School, 675 Hoes Lane West, Piscataway, New Jersey 08854, USA;

    Department of Immunology, University of Washington School of Medicine, 1959 NE Pacific Street,Seattle, Washington 98195, USA;

    Department of Biochemistry, UMDNJ-RWJ Medical School, 675 Hoes Lane West, Piscataway, New Jersey 08854, USA;

    Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, 679 Hoes Lane West, Piscataway, New Jersey 08854, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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