Dataset Information

Dual conformational recognition by Z-DNA binding protein is important for the B-Z transition process.

ABSTRACT: Left-handed Z-DNA is radically different from the most common right-handed B-DNA and can be stabilized by interactions with the Z? domain, which is found in a group of proteins, such as human ADAR1 and viral E3L proteins. It is well-known that most Z? domains bind to Z-DNA in a conformation-specific manner and induce rapid B-Z transition in physiological conditions. Although many structural and biochemical studies have identified the detailed interactions between the Z? domain and Z-DNA, little is known about the molecular basis of the B-Z transition process. In this study, we successfully converted the B-Z transition-defective Z? domain, vvZ?E3L, into a B-Z converter by improving B-DNA binding ability, suggesting that B-DNA binding is involved in the B-Z transition. In addition, we engineered the canonical B-DNA binding protein GH5 into a Z?-like protein having both Z-DNA binding and B-Z transition activities by introducing Z-DNA interacting residues. Crystal structures of these mutants of vvZ?E3L and GH5 complexed with Z-DNA confirmed the significance of conserved Z-DNA binding interactions. Altogether, our results provide molecular insight into how Z? domains obtain unusual conformational specificity and induce the B-Z transition.

SUBMITTER: Park C

PROVIDER: S-EPMC7736808 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Dual conformational recognition by Z-DNA binding protein is important for the B-Z transition process.

Park Chaehee C Zheng Xu X Park Chan Yang CY Kim Jeesoo J Lee Seul Ki SK Won Hyuk H Choi Jinhyuk J Kim Yang-Gyun YG Choi Hee-Jung HJ

Nucleic acids research 20201201 22

Left-handed Z-DNA is radically different from the most common right-handed B-DNA and can be stabilized by interactions with the Zα domain, which is found in a group of proteins, such as human ADAR1 and viral E3L proteins. It is well-known that most Zα domains bind to Z-DNA in a conformation-specific manner and induce rapid B-Z transition in physiological conditions. Although many structural and biochemical studies have identified the detailed interactions between the Zα domain and Z-DNA, little ...[more]

PMID: 33245772

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Project description:Transcription factors recognize specific genomic sequences to regulate complex gene-expression programs. Although it is well-established that transcription factors bind to specific DNA sequences using a combination of base readout and shape recognition, some fundamental aspects of protein-DNA binding remain poorly understood1,2. Many DNA-binding proteins induce changes in the structure of the DNA outside the intrinsic B-DNA envelope. However, how the energetic cost that is associated with distorting the DNA contributes to recognition has proven difficult to study, because the distorted DNA exists in low abundance in the unbound ensemble3-9. Here we use a high-throughput assay that we term SaMBA (saturation mismatch-binding assay) to investigate the role of DNA conformational penalties in transcription factor-DNA recognition. In SaMBA, mismatched base pairs are introduced to pre-induce structural distortions in the DNA that are much larger than those induced by changes in the Watson-Crick sequence. Notably, approximately 10% of mismatches increased transcription factor binding, and for each of the 22 transcription factors that were examined, at least one mismatch was found that increased the binding affinity. Mismatches also converted non-specific sites into high-affinity sites, and high-affinity sites into 'super sites' that exhibit stronger affinity than any known canonical binding site. Determination of high-resolution X-ray structures, combined with nuclear magnetic resonance measurements and structural analyses, showed that many of the DNA mismatches that increase binding induce distortions that are similar to those induced by protein binding-thus prepaying some of the energetic cost incurred from deforming the DNA. Our work indicates that conformational penalties are a major determinant of protein-DNA recognition, and reveals mechanisms by which mismatches can recruit transcription factors and thus modulate replication and repair activities in the cell10,11.

Dataset Information

Dual conformational recognition by Z-DNA binding protein is important for the B-Z transition process.

Publications

Dual conformational recognition by Z-DNA binding protein is important for the B-Z transition process.

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