NMR investigation on the DNA binding and B–Z transition pathway of the Zα domain of human ADAR1

Lee, Yeon-Mi; Kim, Hee‐Eun; Lee, Eun-Hae; Seo, Young-Jun; Lee, Ae-Ree; Lee, Joon‐Hwa

doi:10.1016/j.bpc.2012.12.002

Cited by 11 publications

(8 citation statements)

References 18 publications

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“…Given this observation, how does the positive charge in the β-wing affect the B-to-Z transition rate? It was proposed that Zα bind to B-DNA prior to the transition to Z-DNA (40,41), so the association rate of Zα to DNA possibly contributes to the B-to-Z transition rate. Under this hypothesis, it is expected that a positively charged residue can enhance the transition rate by increasing the association of negatively charged DNA molecules to the positively charged protein molecules (42).…”

Section: Resultsmentioning

confidence: 99%

Distinct Z-DNA binding mode of a PKR-like protein kinase containing a Z-DNA binding domain (PKZ)

Kim

Hur

Park

et al. 2014

Nucleic Acids Research

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Double-stranded ribonucleic acid-activated protein kinase (PKR) downregulates translation as a defense mechanism against viral infection. In fish species, PKZ, a PKR-like protein kinase containing left-handed deoxyribonucleic acid (Z-DNA) binding domains, performs a similar role in the antiviral response. To understand the role of PKZ in Z-DNA recognition and innate immune response, we performed structural and functional studies of the Z-DNA binding domain (Zα) of PKZ from Carassius auratus (caZαPKZ). The 1.7-Å resolution crystal structure of caZαPKZ:Z-DNA revealed that caZαPKZ shares the overall fold with other Zα, but has discrete structural features that differentiate its DNA binding mode from others. Functional analyses of caZαPKZ and its mutants revealed that caZαPKZ mediates the fastest B-to-Z transition of DNA among Zα, and the minimal interaction for Z-DNA recognition is mediated by three backbone phosphates and six residues of caZαPKZ. Structure-based mutagenesis and B-to-Z transition assays confirmed that Lys56 located in the β-wing contributes to its fast B-to-Z transition kinetics. Investigation of the DNA binding kinetics of caZαPKZ further revealed that the B-to-Z transition rate is positively correlated with the association rate constant. Taking these results together, we conclude that the positive charge in the β-wing largely affects fast B-to-Z transition activity by enhancing the DNA binding rate.

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Section: Resultsmentioning

confidence: 99%

Distinct Z-DNA binding mode of a PKR-like protein kinase containing a Z-DNA binding domain (PKZ)

Kim

Hur

Park

et al. 2014

Nucleic Acids Research

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“…A crystal structural study of a DNA duplex complexed with Zα ADAR1 showed that bases between B- and Z-DNA are almost continuously stacked, with the extrusion of one base-pair at the B-Z junction [97]. Hydrogen exchange studies of the DNA-Zα ADAR1 complexes showed that the k ex values of the A·T base-pairs in AT-rich regions increased as the P/N ratio increased, indicating that Zα ADAR1 significantly destabilizes AT-rich regions [49,98]. However, Zα ADAR1 had little effect on the k ex values of the G·C base-pairs in CG-rich regions [49,98].…”

Section: Implications For Dna/rna-protein Interactionsmentioning

confidence: 99%

Base-pair Opening Dynamics of Nucleic Acids in Relation to Their Biological Function

Choi

Kim

Jin

et al. 2019

Computational and Structural Biotechnology Journal

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Base-pair opening is a conformational transition that is required for proper biological function of nucleic acids. Hydrogen exchange, observed by NMR spectroscopic experiments, is a widely used method to study the thermodynamics and kinetics of base-pair opening in nucleic acids. The hydrogen exchange data of imino protons are analyzed based on a two-state (open/closed) model for the base-pair, where hydrogen exchange only occurs from the open state. In this review, we discuss examples of how hydrogen exchange data provide insight into several interesting biological processes involving functional interactions of nucleic acids: i ) selective recognition of DNA by proteins; ii ) regulation of RNA cleavage by site-specific mutations; iii ) intermolecular interaction of proteins with their target DNA or RNA; iv ) formation of PNA:DNA hybrid duplexes.

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“…These observations led us to question whether Z-DNA states influence the threshold for experience-dependent transcriptional activity, which itself is critical for at least the first stage of memory consolidation 12 . Given that Adar1 recognizes Z-DNA in vitro 13 , and potentially alters the formation of Z-DNA 14 , 15 , we hypothesized that Adar1-mediated changes in DNA structure states are critical for learning-induced gene expression in the adult brain and that this impacts the formation of fear extinction memory, an important form of memory that is dependent on rapid changes in gene expression 16 and on behavioral flexibility following extinction learning 17 . In confirmation of this hypothesis we observed that Z-DNA is dynamic in response to fear extinction learning, with manipulation of Z-DNA by doxorubicin impairing extinction when infused into the infralimbic PFC.…”

Section: Introductionmentioning

confidence: 99%

Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction

Marshall

Zhao

et al. 2020

Nat Neurosci

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DNA forms conformational states beyond the right-handed double-helix; however, the functional relevance of these non-canonical structures in the brain remains unknown. We show that, in the prefrontal cortex of mice, the formation of one such structure, Z-DNA, is involved in the regulation of extinction memory. Z-DNA is formed during fear learning, and reduced during extinction learning, which is mediated, in part, by a direct interaction between Z-DNA and the RNA editing enzyme Adar1. Adar1 binds to Z-DNA during fear extinction learning which leads to a reduction in Z-DNA at sites where Adar1 is recruited. Knockdown of Adar1 leads to an inability to modify a previously acquired fear memory and blocks activity-dependent changes in DNA structure and RNA state; effects that are fully rescued by the introduction of full-length Adar1. These findings suggest a novel mechanism of learning-induced gene regulation dependent on both proteins which recognize DNA structure, and the state.

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NMR investigation on the DNA binding and B–Z transition pathway of the Zα domain of human ADAR1

Cited by 11 publications

References 18 publications

Distinct Z-DNA binding mode of a PKR-like protein kinase containing a Z-DNA binding domain (PKZ)

Distinct Z-DNA binding mode of a PKR-like protein kinase containing a Z-DNA binding domain (PKZ)

Base-pair Opening Dynamics of Nucleic Acids in Relation to Their Biological Function

Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction

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