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Nat Commun. 2018 Dec 18;9(1):5366. doi: 10.1038/s41467-018-07780-z.

HDX-MS reveals dysregulated checkpoints that compromise discrimination against self RNA during RIG-I mediated autoimmunity.

Author information

1
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA. jzheng@scripps.edu.
2
Structural Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
3
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA.
4
Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, 08854, USA.
5
The Center for Computational Biology, The Scripps Research Institute, Jupiter, FL, 33458, USA.
6
Omics Informatics LLC, Honolulu, HI 96813, USA.
7
Structural Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. joseph.marcotrigiano@nih.gov.
8
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, 33458, USA. pgriffin@scripps.edu.

Abstract

Retinoic acid inducible gene-I (RIG-I) ensures immune surveillance of viral RNAs bearing a 5'-triphosphate (5'ppp) moiety. Mutations in RIG-I (C268F and E373A) lead to impaired ATPase activity, thereby driving hyperactive signaling associated with autoimmune diseases. Here we report, using hydrogen/deuterium exchange, mechanistic models for dysregulated RIG-I proofreading that ultimately result in the improper recognition of cellular RNAs bearing 7-methylguanosine and N1-2'-O-methylation (Cap1) on the 5' end. Cap1-RNA compromises its ability to stabilize RIG-I helicase and blunts caspase activation and recruitment domains (CARD) partial opening by threefold. RIG-I H830A mutation restores Cap1-helicase engagement as well as CARDs partial opening event to a level comparable to that of 5'ppp. However, E373A RIG-I locks the receptor in an ATP-bound state, resulting in enhanced Cap1-helicase engagement and a sequential CARDs stimulation. C268F mutation renders a more tethered ring architecture and results in constitutive CARDs signaling in an ATP-independent manner.

PMID:
30560918
PMCID:
PMC6299088
DOI:
10.1038/s41467-018-07780-z
[Indexed for MEDLINE]
Free PMC Article

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