How do ADARs bind RNA? New protein‐RNA structures illuminate substrate recognition by the RNA editing ADARs

• Published in: BioEssays Vol. 39; no. 4; pp. np - n/a
• Main Authors: Thomas, Justin M., Beal, Peter A.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.04.2017
• Subjects: active sites; ADAR; Adenosine; Adenosine Deaminase - metabolism; Amino acid substitution; Amino acids; Catalytic Domain; Crystal structure; Deamination; Domains; Double-stranded RNA; Editing; Enzymes; epitranscriptome; genome; Genomes; Humans; messenger RNA; Models, Molecular; mRNA; Protein Conformation; Proteins; recoding; Recognition; RNA - metabolism; RNA Editing; RNA-Binding Proteins - metabolism; Substitution reactions; Substrate Specificity; Substrates; RNA editing; ADAR; epitranscriptome; recoding
• ISSN: 0265-9247; 1521-1878; 1521-1878
• DOI: 10.1002/bies.201600187

Deamination of adenosine in RNA to form inosine has wide ranging consequences on RNA function including amino acid substitution to give proteins not encoded in the genome. What determines which adenosines in an mRNA are subject to this modification reaction? The answer lies in an understanding of the mechanism and substrate recognition properties of adenosine deaminases that act on RNA (ADARs). Our recent publication of X‐ray crystal structures of the human ADAR2 deaminase domain bound to RNA editing substrates shed considerable light on how the catalytic domains of these enzymes bind RNA and promote adenosine deamination. Here we review in detail the deaminase domain‐RNA contact surfaces and present models of how full length ADARs, bearing double stranded RNA‐binding domains (dsRBDs) and deaminase domains, could process naturally occurring substrate RNAs. Editing of dsRNA by ADARs has a profound effect on the properties of RNA. Editing is selective and dependent on the interaction of RNA with multiple ADAR domains. Here we review the interactions of the ADAR2 catalytic domain with dsRNA and propose new models for concurrent binding with dsRBDs.