Differential Structural Features of Two Mutant ADAR1p150 Za Domains Associated with Aicardi-Goutie`res Syndrome

The Za 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. ?? 2023 Elsevier Ltd. All rights reserved.

Automated summary

The Za domain of ADARp150 is crucial for proper Z-RNA binding and plays a key role in the type-I interferon response pathway. Two point mutations (N173S and P193A) in this domain are associated with decreased A-to-I editing in neurodegenerative disorders. Biophysical and structural characterization of these mutated domains revealed a lower affinity for Z-RNA binding, which can be explained by structural changes in the beta-wing and alterations in protein dynamics.