Differential Structural Features of Two Mutant ADAR1p150 Zα Domains Associated with Aicardi-Goutières Syndrome

J Mol Biol. 2023 Apr 15;435(8):168040. doi: 10.1016/j.jmb.2023.168040. Epub 2023 Mar 7.

Abstract

The Zα domain of ADARp150 is critical for proper Z-RNA substrate binding and is a key factor in the type-I interferon response pathway. Two point-mutations in this domain (N173S and P193A), which cause neurodegenerative disorders, are linked to decreased A-to-I editing in disease models. To understand this phenomenon at the molecular level, we biophysically and structurally characterized these two mutated domains, revealing that they bind Z-RNA with a decreased affinity. Less efficient binding to Z-RNA can be explained by structural changes in beta-wing, part of the Z-RNA-protein interface, and alteration of conformational dynamics of the proteins.

Keywords: ADAR1; Aicardi-Goutières syndrome; Biophysics; RNA recognition; Z-RNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Deaminase* / chemistry
  • Adenosine Deaminase* / genetics
  • Adenosine Deaminase* / metabolism
  • Autoimmune Diseases of the Nervous System* / enzymology
  • Autoimmune Diseases of the Nervous System* / genetics
  • Binding Sites
  • Humans
  • Nervous System Malformations* / enzymology
  • Nervous System Malformations* / genetics
  • Nucleic Acid Conformation
  • Point Mutation
  • Protein Domains / genetics
  • RNA / chemistry

Substances

  • Adenosine Deaminase
  • RNA
  • ADAR protein, human

Supplementary concepts

  • Aicardi-Goutieres syndrome