Intrinsic DNA Shape Accounts for Affinity Differences between Hox-Cofactor Binding Sites

Zeiske, Tim; Baburajendran, Nithya; Kaczynska, Anna; Brasch, Julia; Palmer, Arthur G.; Shapiro, Lawrence; Mann, Richard S.

doi:10.1016/j.celrep.2018.07.100

Cited by 37 publications

(36 citation statements)

References 44 publications

(80 reference statements)

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“…Furthermore, the bases at this position have a significant influence on the local DNA shape, with a narrow DNA minor groove width (MGW) in the unbound state correlating with high affinity DNA-binding of WUS by the insertion of the conserved R38 into the minor groove. These findings are consistent with other examples of HD-DNA interactions showing that local optima in the DNA structure are preferentially recognized 9,36 . Besides DNA methylation, other epigenetic modifications, such as histone modifications, dynamically control gene expression and thereby play an important role in maintaining cellular identity 48 .…”

Section: Members Of Wus and Tale Subfamily Of Hd-tfs In Plants Have Bsupporting

confidence: 91%

“…Why does the +1 DNA motif position have such a strong influence on WUS-HD affinity, despite the fact that this base is not involved in hydrogen bond interactions? Since DNA shape can have a substantial effect on specificity and affinity of HD-DNA complexes 36 , we computationally investigated potential structural differences in the DNA sequences experimentally tested. To this end, we used the DNAShape tool 37 to predict the intrinsic conformation of unbound DNA probes differing in the +1 position focusing on minor groove width (MGW) (Fig.…”

Section: Wus-hd Binding Specificity Depends On Dna Shapementioning

confidence: 99%

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Structural basis for the complex DNA binding behavior of the plant stem cell regulator WUSCHEL

Sloan

Hankenjos

Gebert

et al. 2020

Preprint

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AbstractStem cells are one of the foundational evolutionary novelties that allowed the independent emergence of multicellularity in the plant and animal lineages. In plants, the homeodomain (HD) transcription factor WUSCHEL (WUS) is essential for the maintenance of stem cells in the shoot apical meristem. WUS has been reported to bind to diverse DNA motifs and to act as transcriptional activator and repressor. However, the mechanisms underlying this remarkable behavior have remained unclear. Here, we quantitatively delineate WUS binding to three divergent DNA motifs and resolve the relevant structural underpinnings. We show that WUS exhibits a strong binding preference for TGAA repeat sequences, while retaining the ability to weakly bind to TAAT elements. This behavior is attributable the formation of dimers through interactions of specific residues in the HD that stabilize WUS DNA interaction. Our results provide a mechanistic basis for dissecting WUS dependent regulatory networks in plant stem cell control.

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Section: Members Of Wus and Tale Subfamily Of Hd-tfs In Plants Have Bsupporting

confidence: 91%

Section: Wus-hd Binding Specificity Depends On Dna Shapementioning

confidence: 99%

Structural basis for the complex DNA binding behavior of the plant stem cell regulator WUSCHEL

Sloan

Hankenjos

Gebert

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…can have a substantial effect on specificity and affinity of HD-DNA complexes 36 , we computationally investigated potential structural differences in the DNA sequences experimentally tested. To this end, we used the DNAShape tool 37 to predict the intrinsic conformation of unbound DNA probes differing in the +1 position focusing on minor groove width (MGW) (Fig.…”

Section: Wus Has a Canonical Hd Fold With Unique Structural Featuresmentioning

confidence: 99%

Structural basis for the complex DNA binding behavior of the plant stem cell regulator WUSCHEL

et al. 2020

View full text Add to dashboard Cite

Stem cells are one of the foundational evolutionary novelties that allowed the independent emergence of multicellularity in the plant and animal lineages. In plants, the homeodomain (HD) transcription factor WUSCHEL (WUS) is essential for the maintenance of stem cells in the shoot apical meristem. WUS has been reported to bind to diverse DNA motifs and to act as transcriptional activator and repressor. However, the mechanisms underlying this remarkable behavior have remained unclear. Here, we quantitatively delineate WUS binding to three divergent DNA motifs and resolve the relevant structural underpinnings. We show that WUS exhibits a strong binding preference for TGAA repeat sequences, while retaining the ability to weakly bind to TAAT elements. This behavior is attributable to the formation of dimers through interactions of specific residues in the HD that stabilize WUS DNA interaction. Our results provide a mechanistic basis for dissecting WUS dependent regulatory networks in plant stem cell control.

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“…S1; Tables S1,S2). The energy cost required to distort DNA must come from favorable intermolecular contacts that form upon complex formation 13,14 . This energetic cost could vary with sequence and contribute to protein-DNA binding affinity and selectivity 2,15,16 .…”

Section: Main Textmentioning

confidence: 99%

DNA mismatches reveal widespread conformational penalties in protein-DNA recognition

Afek

Shi

Rangadurai

et al. 2019

Preprint

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Transcription-factor (TF) proteins recognize specific genomic sequences, despite an overwhelming excess of non-specific DNA, to regulate complex gene expression programs 1-3 . While there have been significant advances in understanding how DNA sequence and shape contribute to recognition, some fundamental aspects of protein-DNA binding remain poorly understood 2,3 . Many DNA-binding proteins induce changes in the DNA structure outside the intrinsic B-DNA envelope. How the energetic cost associated with distorting DNA contributes to recognition has proven difficult to study and measure experimentally because the distorted DNA structures exist as low-abundance conformations in the naked B-DNA ensemble 4-10 . Here, we use a novel high-throughput assay called SaMBA (Saturation Mismatch-Binding Assay) to investigate the role of DNA conformational penalties in TF-DNA recognition. The approach introduces mismatched base-pairs (i.e. mispairs) within TF binding sites to pre-induce a variety of DNA structural distortions much larger than those induced by changes in Watson-Crick sequence.Strikingly, while most mismatches either weakened TF binding (~70%) or had negligible effects (~20%), approximately 10% of mismatches increased binding and at least one mismatch was found that increased the binding affinity for each of 21 examined TFs. Mismatches also converted sites from the non-specific affinity range into specific sites, and high-affinity sites into "super-sites" stronger than any known canonical binding site. These findings reveal a complex binding landscape that cannot be explained based on DNA sequence alone. Analysis of crystal structures together with NMR and molecular dynamics simulations revealed that many of the mismatches that increase binding induce distortions similar to those induced by TF binding, thus pre-paying some of the energetic cost to deform the DNA. Our work indicates that conformational penalties are a major determinant of protein-DNA recognition, and reveals mechanisms by which mismatches can recruit TFs and thus modulate replication and repair activities in the cell 11,12 .

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Intrinsic DNA Shape Accounts for Affinity Differences between Hox-Cofactor Binding Sites

Cited by 37 publications

References 44 publications

Structural basis for the complex DNA binding behavior of the plant stem cell regulator WUSCHEL

Structural basis for the complex DNA binding behavior of the plant stem cell regulator WUSCHEL

Structural basis for the complex DNA binding behavior of the plant stem cell regulator WUSCHEL

DNA mismatches reveal widespread conformational penalties in protein-DNA recognition

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