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PDBsum entry 5f9h
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Hydrolase/RNA
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PDB id
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5f9h
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References listed in PDB file
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Key reference
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Title
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Structural basis for m7g recognition and 2'-O-Methyl discrimination in capped rnas by the innate immune receptor rig-I.
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Authors
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S.C.Devarkar,
C.Wang,
M.T.Miller,
A.Ramanathan,
F.Jiang,
A.G.Khan,
S.S.Patel,
J.Marcotrigiano.
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Ref.
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Proc Natl Acad Sci U S A, 2016,
113,
596-601.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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RNAs with 5'-triphosphate (ppp) are detected in the cytoplasm principally by the
innate immune receptor Retinoic Acid Inducible Gene-I (RIG-I), whose activation
triggers a Type I IFN response. It is thought that self RNAs like mRNAs are not
recognized by RIG-I because 5'ppp is capped by the addition of a 7-methyl
guanosine (m7G) (Cap-0) and a 2'-O-methyl (2'-OMe) group to the 5'-end
nucleotide ribose (Cap-1). Here we provide structural and mechanistic basis for
exact roles of capping and 2'-O-methylation in evading RIG-I recognition.
Surprisingly, Cap-0 and 5'ppp double-stranded (ds) RNAs bind to RIG-I with
nearly identical Kd values and activate RIG-I's ATPase and cellular signaling
response to similar extents. On the other hand, Cap-0 and 5'ppp single-stranded
RNAs did not bind RIG-I and are signaling inactive. Three crystal structures of
RIG-I complexes with dsRNAs bearing 5'OH, 5'ppp, and Cap-0 show that RIG-I can
accommodate the m7G cap in a cavity created through conformational changes in
the helicase-motif IVa without perturbing the ppp interactions. In contrast,
Cap-1 modifications abrogate RIG-I signaling through a mechanism involving the
H830 residue, which we show is crucial for discriminating between Cap-0 and
Cap-1 RNAs. Furthermore, m7G capping works synergistically with 2'-O-methylation
to weaken RNA affinity by 200-fold and lower ATPase activity. Interestingly, a
single H830A mutation restores both high-affinity binding and signaling activity
with 2'-O-methylated dsRNAs. Our work provides new structural insights into the
mechanisms of host and viral immune evasion from RIG-I, explaining the
complexity of cap structures over evolution.
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