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

Autor: Langeberg CJ; Department of Biochemistry and Molecular Genetics and RNA Bioscience Initiative, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA. Electronic address: CONNER.LANGEBERG@CUANSCHUTZ.EDU., Nichols PJ; Department of Biochemistry and Molecular Genetics and RNA Bioscience Initiative, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA. Electronic address: PARKER.NICHOLS@CUANSCHUTZ.EDU., Henen MA; Department of Biochemistry and Molecular Genetics and RNA Bioscience Initiative, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: MORKOS.HENEN@CUANSCHUTZ.EDU., Vicens Q; Department of Biochemistry and Molecular Genetics and RNA Bioscience Initiative, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; RNA Bioscience Initiative, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA. Electronic address: QUENTIN.VICENS@CUANSCHUTZ.EDU., Vögeli B; Department of Biochemistry and Molecular Genetics and RNA Bioscience Initiative, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA; RNA Bioscience Initiative, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA. Electronic address: BEAT.VOGELI@CUANSCHUTZ.EDU.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2023 Apr 15; Vol. 435 (8), pp. 168040. Date of Electronic Publication: 2023 Mar 07.
DOI: 10.1016/j.jmb.2023.168040
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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