DNA/RNA molecules adopting the left-handed conformation (Z-form) have been attributed with immunogenic properties. However, their biological role and importance have been a topic of debate for many years. The discovery of Z-DNA/RNA binding domains (Zα domains) in varied proteins that are involved in the innate immune response, such as the interferon inducible form of the RNA editing enzyme ADAR1 (p150), Z-DNA binding protein 1 (ZBP1), the fish kinase PKZ and the poxvirus inhibitor of interferon response E3L, indicates important roles of Z-DNA/RNA in immunity and self/non-self-discrimination. Such Zα domain-containing proteins recognize left-handed Z-DNA/RNA in a conformation-specific manner. Recent studies have implicated these domains in virus recognition. Given these important emerging roles for the Zα domains, it is pivotal to understand the mechanism of recognition of the Z-DNA/Z-RNA by these domains. To this end, we assessed the binding thermodynamics of Zα domain from ORF112 and ADAR1 on T(CG)3 and T(CG)6 oligonucleotides which have high propensity to adopt the Z-conformation. Our study highlights important differences in the mode of oligonucleotide binding by the two Zα domains originating from different proteins. Site-directed mutagenesis was employed together with isothermal titration calorimetry to tease apart finer details of the binding thermodynamics. Our work advances the understanding on binding thermodynamics of Zα domains to their cognate nucleic acid substrates and paves the ground for future efforts to gain a complete appreciation of this process.
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Platelet hyperactivation noted in an individual with Long COVID and with severe platelet hyperactivation. Platelet pathology and hyperactivation, together with fibrin amyloid microclot formation, may be central in chronic ischaemia-reperfusion injury. Read more in “The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, long COVID and ME/CFS…” from Professors Douglas Kell and Etheresia Pretorius on pages 1653 – 1708.
Research Article|
August 31 2022
Thermodynamic analysis of Zα domain-nucleic acid interactions
Bharath Srinivasan
;
Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing - original draft
Instituto Gulbenkian de Ciência, Rua Quinta Grande 6, Oeiras 2781-156, Portugal
Correspondence: Krzysztof Kuś (krzysztof.kus@bioch.ox.ac.uk) or Bharath Srinivasan (bharath.srinivasan@astrazeneca.com)
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Krzysztof Kuś;
Conceptualization, Resources, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - review & editing
Instituto Gulbenkian de Ciência, Rua Quinta Grande 6, Oeiras 2781-156, Portugal
Correspondence: Krzysztof Kuś (krzysztof.kus@bioch.ox.ac.uk) or Bharath Srinivasan (bharath.srinivasan@astrazeneca.com)
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Alekos Athanasiadis
Alekos Athanasiadis
Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Validation, Project administration
Instituto Gulbenkian de Ciência, Rua Quinta Grande 6, Oeiras 2781-156, Portugal
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Publisher: Portland Press Ltd
Received:
April 25 2022
Revision Received:
August 08 2022
Accepted:
August 12 2022
Accepted Manuscript online:
August 15 2022
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2022
Biochem J (2022) 479 (16): 1727–1741.
Article history
Received:
April 25 2022
Revision Received:
August 08 2022
Accepted:
August 12 2022
Accepted Manuscript online:
August 15 2022
Citation
Bharath Srinivasan, Krzysztof Kuś, Alekos Athanasiadis; Thermodynamic analysis of Zα domain-nucleic acid interactions. Biochem J 31 August 2022; 479 (16): 1727–1741. doi: https://doi.org/10.1042/BCJ20220200
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