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

• Published in: Journal of molecular biology Vol. 435; no. 8; p. 168040
• Main Authors: Langeberg, Conner J., Nichols, Parker J., Henen, Morkos A., Vicens, Quentin, Vögeli, Beat
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 15.04.2023
• Subjects: ADAR1; Adenosine Deaminase - chemistry; Adenosine Deaminase - genetics; Adenosine Deaminase - metabolism; Aicardi-Goutières syndrome; Autoimmune Diseases of the Nervous System - enzymology; Autoimmune Diseases of the Nervous System - genetics; Binding Sites; Biophysics; Humans; Nervous System Malformations - enzymology; Nervous System Malformations - genetics; Nucleic Acid Conformation; Point Mutation; Protein Domains - genetics; RNA - chemistry; RNA recognition; Z-RNA; RNA recognition; Biophysics; Z-RNA; ADAR1; Aicardi-Goutières syndrome
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2023.168040

[Display omitted] •The Zα domain of the ADAR1 isoform ADARp150 is critical for the innate immune response.•Zα point-mutations N173S and P193A cause Aicardi-Goutières Syndrome.•Zα mutants bind Z-RNA with decreased affinity.•Mutations change Z-RNA-protein interface structure and conformational dynamics. 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.