Effects of Aicardi-Goutières syndrome mutations predicted from ADAR-RNA structures

Andrew J Fisher, Peter A. Beal

Research output: Contribution to journalReview article

6 Citations (Scopus)

Abstract

Adenosine (A) to inosine (I) RNA editing is important for life in metazoan organisms. Dysregulation or mutations that compromise the efficacy of A to I editing results in neurological disorders and a shorten life span. These reactions are catalyzed by adenosine deaminases acting on RNA (ADARs), which hydrolytically deaminate adenosines in regions of duplex RNA. Because inosine mimics guanosine in hydrogen bonding, this prolific RNA editing alters the sequence and structural information in the RNA landscape. Aicardi-Goutières syndrome (AGS) is a severe childhood autoimmune disease that is one of a broader set of inherited disorders characterized by constitutive upregulation of type I interferon (IFN) referred to as type I interferonopathies. AGS is caused by mutations in multiple genes whose protein products, including ADAR1, are all involved in nucleic acid metabolism or sensing. The recent crystal structures of human ADAR2 deaminase domain complexed with duplex RNA substrates enabled modeling of how AGS causing mutations may influence RNA binding and catalysis. The mutations can be broadly characterized into three groups; mutations on RNA-binding loops that directly affect RNA binding, “second-layer” mutations that can alter the disposition of RNA-binding loops, and mutations that can alter the position of an α-helix bearing an essential catalytic residue.

Original languageEnglish (US)
Pages (from-to)164-170
Number of pages7
JournalRNA Biology
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

Aicardi Syndrome
Adenosine Deaminase
RNA
Mutation
RNA Editing
Inosine
Adenosine
Interferon Type I
Guanosine
Hydrogen Bonding
Nervous System Diseases
Catalysis
Nucleic Acids
Autoimmune Diseases
Up-Regulation

Keywords

  • ADAR; Aicardi-Goutieres Syndrome; base-flipping; A to I; inosine; RNA editing

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Effects of Aicardi-Goutières syndrome mutations predicted from ADAR-RNA structures. / Fisher, Andrew J; Beal, Peter A.

In: RNA Biology, Vol. 14, No. 2, 01.02.2017, p. 164-170.

Research output: Contribution to journalReview article

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