Conformational rearrangements of RIG-I receptor on formation of a multiprotein:dsRNA assembly

The retinoic acid inducible gene-I (RIG-I)-like family of receptors is positioned at the front line of our innate cellular defence system. RIG-I detects and binds to foreign duplex RNA in the cytoplasm of both immune and non-immune cells, and initiates the induction of type I interferons and pro-inf...

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Bibliographic Details
Published in:Nucleic acids research 2013-03, Vol.41 (5), p.3436-3445
Main Authors: Beckham, Simone A, Brouwer, Jason, Roth, Anna, Wang, Die, Sadler, Anthony J, John, Matthias, Jahn-Hofmann, Kerstin, Williams, Bryan R G, Wilce, Jacqueline A, Wilce, Matthew C J
Format: Article
Language:English
Subjects:
Apoproteins - chemistry
Chromatography, Gel
DEAD Box Protein 58
DEAD-box RNA Helicases - chemistry
Humans
Models, Molecular
Peptide Fragments - chemistry
Protein Binding
Protein Structure, Quaternary
Protein Structure, Secondary
Protein Structure, Tertiary
Proteolysis
Receptors, Immunologic
RNA, Double-Stranded - chemistry
Scattering, Small Angle
Structural Biology
Trypsin - chemistry
X-Ray Diffraction
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Summary:The retinoic acid inducible gene-I (RIG-I)-like family of receptors is positioned at the front line of our innate cellular defence system. RIG-I detects and binds to foreign duplex RNA in the cytoplasm of both immune and non-immune cells, and initiates the induction of type I interferons and pro-inflammatory cytokines. The mechanism of RIG-I activation by double-stranded RNA (dsRNA) involves a molecular rearrangement proposed to expose the N-terminal pair of caspase activation recruitment domains, enabling an interaction with interferon-beta promoter stimulator 1 (IPS-1) and thereby initiating downstream signalling. dsRNA is particularly stimulatory when longer than 20 bp, potentially through allowing binding of more than one RIG-I molecule. Here, we characterize full-length RIG-I and RIG-I subdomains combined with a stimulatory 29mer dsRNA using multi-angle light scattering and size-exclusion chromatography-coupled small-angle X-ray scattering, to build up a molecular model of RIG-I before and after the formation of a 2:1 protein:dsRNA assembly. We report the small-angle X-ray scattering-derived solution structure of the human apo-RIG-I and observe that on binding of RIG-I to dsRNA in a 2:1 ratio, the complex becomes highly extended and flexible. Hence, here we present the first model of the fully activated oligomeric RIG-I.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gks1477