NMR study of the Z-DNA binding mode and B–Z transition activity of the Zα domain of human ADAR1 when perturbed by mutation on the α3 helix and β-hairpin

Jeong, Minjee; Lee, Ae-Ree; Kim, Hee‐Eun; Choi, Yong-Geun; Choi, Byong‐Seok; Lee, Joon‐Hwa

doi:10.1016/j.abb.2014.06.026

Cited by 12 publications

(11 citation statements)

References 23 publications

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“…8, B-D). This is consistent with previous mutagenesis and NMR studies (26,27) that show the importance of the above mentioned residues in facilitating the interaction between the two. However, a minor difference in the nature of interaction is also seen.…”

Section: Simulation Retains the Conserved Interactions Between Hz␣supporting

confidence: 93%

A B–Z junction induced by an A … A mismatch in GAC repeats in the gene for cartilage oligomeric matrix protein promotes binding with the hZαADAR1 protein

Kolimi

Ajjugal

Rathinavelan

2017

Journal of Biological Chemistry

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GAC repeat expansion from five to seven in the exonic region of the gene for cartilage oligomeric matrix protein (COMP) leads to pseudoachondroplasia, a skeletal abnormality. However, the molecular mechanism by which GAC expansions in the gene lead to skeletal dysplasias is poorly understood. Here we used molecular dynamics simulations, which indicate that an A … A mismatch in a d(GAC)·d(GAC) duplex induces negative supercoiling, leading to a local B-to-Z DNA transition. This transition facilitates the binding of d(GAC)·d(GAC) with the Zα-binding domain of human adenosine deaminase acting on RNA 1 (ADAR1, hZα), as confirmed by CD, NMR, and microscale thermophoresis studies. The CD results indicated that hZα recognizes the zigzag backbone of d(GAC)·d(GAC) at the B-Z junction and subsequently converts it into Z-DNA via the so-called passive mechanism. Molecular dynamics simulations carried out for the modeled hZα-d(GAC)d(GAC) complex confirmed the retention of previously reported important interactions between the two molecules. These findings suggest that hZα binding with the GAC hairpin stem in can lead to a non-genetic, RNA editing-mediated substitution in COMP that may then play a crucial role in the development of pseudoachondroplasia.

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Section: Simulation Retains the Conserved Interactions Between Hz␣supporting

confidence: 93%

A B–Z junction induced by an A … A mismatch in GAC repeats in the gene for cartilage oligomeric matrix protein promotes binding with the hZαADAR1 protein

Kolimi

Ajjugal

Rathinavelan

2017

Journal of Biological Chemistry

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“…8 This study also found that the K170A and R174A mutants significantly destabilize the G2·C5 base pair compared to wt-Zα ADAR1 , even though these mutants could efficiently change B-DNA to left-handed Z-DNA. 8 However, the question of how the mutants on the β-hairpin affect the base pair stabilities of the Z-DNA remains.…”

mentioning

confidence: 52%

NMR Exchange Study of Z-DNA Duplexes Induced by the Zα Domain of Human ADAR1 Containing Mutation on the β-Hairpin

Lee¹,

Jeong²,

Yoo³

et al. 2014

Bulletin of the Korean Chemical Society

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“…K169 and N173 form the direct and water-mediated H-bonds to the dC3pdG4 and dG2pdC3 phosphates, respectively ( Figure 2 a) [ 7 ]. The N173A mutant displays the most dramatic decrease in Z-DNA binding affinity, suggesting that it plays an important role in the Zα function [ 27 , 28 ]. Similarly, the K169A mutant also has a significantly lower Z-DNA binding affinity than a wild-type protein [ 27 , 28 ].…”

Section: Crystal Structures Of Zbps Complexed With Dna Duplexesmentioning

confidence: 99%

“…The N173A mutant displays the most dramatic decrease in Z-DNA binding affinity, suggesting that it plays an important role in the Zα function [ 27 , 28 ]. Similarly, the K169A mutant also has a significantly lower Z-DNA binding affinity than a wild-type protein [ 27 , 28 ]. K170 forms direct H-bonds to the dG4pdC5 and dC5pdG6 phosphates ( Figure 2 a) [ 7 ].…”

Section: Crystal Structures Of Zbps Complexed With Dna Duplexesmentioning

confidence: 99%

“…K170 forms direct H-bonds to the dG4pdC5 and dC5pdG6 phosphates ( Figure 2 a) [ 7 ]. The K170A mutant binds to Z-DNA with a lower affinity than wild-type protein, but better than the K169A and N173A mutants [ 27 , 28 ]. Interestingly, R174 and T191 bind to the furanose oxygens of dG6 and dG2, respectively ( Figure 2 a) [ 7 ].…”

Section: Crystal Structures Of Zbps Complexed With Dna Duplexesmentioning

confidence: 99%

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Thermodynamic Model for B-Z Transition of DNA Induced by Z-DNA Binding Proteins

Lee¹,

Kim²,

Seo³

et al. 2018

Molecules

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Z-DNA is stabilized by various Z-DNA binding proteins (ZBPs) that play important roles in RNA editing, innate immune response, and viral infection. In this review, the structural and dynamics of various ZBPs complexed with Z-DNA are summarized to better understand the mechanisms by which ZBPs selectively recognize d(CG)-repeat DNA sequences in genomic DNA and efficiently convert them to left-handed Z-DNA to achieve their biological function. The intermolecular interaction of ZBPs with Z-DNA strands is mediated through a single continuous recognition surface which consists of an α3 helix and a β-hairpin. In the ZBP-Z-DNA complexes, three identical, conserved residues (N173, Y177, and W195 in the Zα domain of human ADAR1) play central roles in the interaction with Z-DNA. ZBPs convert a 6-base DNA pair to a Z-form helix via the B-Z transition mechanism in which the ZBP first binds to B-DNA and then shifts the equilibrium from B-DNA to Z-DNA, a conformation that is then selectively stabilized by the additional binding of a second ZBP molecule. During B-Z transition, ZBPs selectively recognize the alternating d(CG)n sequence and convert it to a Z-form helix in long genomic DNA through multiple sequence discrimination steps. In addition, the intermediate complex formed by ZBPs and B-DNA, which is modulated by varying conditions, determines the degree of B-Z transition.

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NMR study of the Z-DNA binding mode and B–Z transition activity of the Zα domain of human ADAR1 when perturbed by mutation on the α3 helix and β-hairpin

Cited by 12 publications

References 23 publications

A B–Z junction induced by an A … A mismatch in GAC repeats in the gene for cartilage oligomeric matrix protein promotes binding with the hZαADAR1 protein

A B–Z junction induced by an A … A mismatch in GAC repeats in the gene for cartilage oligomeric matrix protein promotes binding with the hZαADAR1 protein

NMR Exchange Study of Z-DNA Duplexes Induced by the Zα Domain of Human ADAR1 Containing Mutation on the β-Hairpin

Thermodynamic Model for B-Z Transition of DNA Induced by Z-DNA Binding Proteins

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