Crystal Structure of PU.1/IRF-4/DNA Ternary Complex

Escalante, Carlos; Brass, Abraham L.; Pongubala, Jagan M.R.; Shatova, Ella; Shen, Leyi; Singh, Harinder; Aggarwal, Aneel K.

doi:10.1016/s1097-2765(02)00703-7

Cited by 151 publications

(151 citation statements)

References 39 publications

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“…Indeed, a DNA oligonucleotide containing an IRF4 consensus binding site identical to that seen in the CD38 gene (5 0 AAGT GAAAC 3 0 ) was used to crystallise the DNA binding domain of IRF4. 7 These data suggest a plausible mechanism by which IRF4 could affect CD38 expression. IRF4 genotype was significantly associated with TFS (P ¼ 0.015; Figure 1b).…”

mentioning

confidence: 85%

Variant IRF4/MUM1 associates with CD38 status and treatment-free survival in chronic lymphocytic leukaemia

et al. 2010

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mentioning

confidence: 85%

Variant IRF4/MUM1 associates with CD38 status and treatment-free survival in chronic lymphocytic leukaemia

et al. 2010

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“…In this protein, the two contiguous DNA binding modules when expressed as separate peptides are able to reciprocally increase the affinity of each other at the composite DNA binding site, even in the absence of any direct contact (18). Intriguingly, in these two cases, as well as several others, allosteric modulation often positively contributes ~10-fold or ~1.5 kcal/mol to assembly of the partner proteins (9,11,(14)(15)(16)(17)(18)(19)(20)(21)(22). This is the same scale at which DNA deformation caused by hairpin polyamides contribute to Exd binding.…”

Section: Global Implicationsmentioning

confidence: 99%

Targeted Chemical Wedges Reveal the Role of Allosteric DNA Modulation in Protein−DNA Assembly

et al. 2008

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The cooperative assembly of multiprotein complexes results from allosteric modulations of DNA structure as well as direct intermolecular contacts between proteins. Such cooperative binding plays a critical role in imparting exquisite sequence specificity on the homeobox transcription factor (Hox) family of developmental transcription factors. A well-characterized example includes the interaction of Hox proteins with extradenticle (Exd), a highly conserved DNA binding transcription factor. Although direct interactions are important, the contribution of indirect interactions toward cooperative assembly of Hox and Exd remains unresolved. Here we use minor groove binding polyamides as structural wedges to induce perturbations at specific base steps within the Exd binding site. We find that allosteric modulation of DNA structure contributes nearly 1.5 kcal/mol to the binding of Exd to DNA, even in the absence of direct Hox contacts. In contrast to previous studies, the sequence-targeted chemical wedges reveal the role of DNA geometry in cooperative assembly of Hox-Exd complexes. Programmable polyamides may well serve as general probes to investigate the role of DNA modulation in the cooperative and highly specific assembly of other protein-DNA complexes.The physical basis of DNA sequence recognition by its ligands (proteins or small molecules) has been investigated in great detail over the years, and several underlying principles have been defined (1-3). The main contributors to the specificity of DNA sequence recognition are interactions between protein side chains and the edges of the base pairs in the cognate DNA site. Efforts to rationally redesign these direct interactions have yielded some exciting successes (4-8). A major limitation of focusing on re-engineering direct interactions, however, is that recognition of sequence-dependent structural properties of DNA and other modes of indirect readout are also critical specificity determinants (9-15). Often a combination of direct and indirect interactions governs exquisite DNA sequence specificity displayed by its ligands (9,11,(14)(15)(16)(17)(18)(19)(20)(21)(22). Specificity in molecular recognition is also achieved by cooperative binding of multiple proteins to closely appositioned DNA sequences (23). Binding of one protein to its DNA cognate site in the enhancer can alter DNA structure and conformational flexibility of a juxtaposed site, thus allosterically improving the energetics

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“…The four letter codes following the references are PDB structure identifiers of TF complexes with binding sites that match the associated motifs. [26] references a crystal structure that is not available in the PDB. To evaluate the quality of the CNE-enriched predictions, we compared them with positive control sets of known TF complex motifs and TF-TF binding site arrangements in crystal structures whose binding sites had high-scoring matches to TF motifs in our PWM library.…”

Section: Resultsmentioning

confidence: 99%

“…A second set of 24 TF-TF -DNA structures and their patterns was constructed from the PDB and one published structure absent from the PDB [26]. For each motif, we required that the observed TF complex motif arrangement (orientation and spacer) be supported by either a TF complex structure or multiple, validated binding sequences.…”

Section: (D) Performing the Genomic Screenmentioning

confidence: 99%

Structure-aided prediction of mammalian transcription factor complexes in conserved non-coding elements

Guturu

Doxey

Wenger

et al. 2013

Phil. Trans. R. Soc. B

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Mapping the DNA-binding preferences of transcription factor (TF) complexes is critical for deciphering the functions of cis -regulatory elements. Here, we developed a computational method that compares co-occurring motif spacings in conserved versus unconserved regions of the human genome to detect evolutionarily constrained binding sites of rigid TF complexes. Structural data were used to estimate TF complex physical plausibility, explore overlapping motif arrangements seldom tackled by non-structure-aware methods, and generate and analyse three-dimensional models of the predicted complexes bound to DNA. Using this approach, we predicted 422 physically realistic TF complex motifs at 18% false discovery rate, the majority of which (326, 77%) contain some sequence overlap between binding sites. The set of mostly novel complexes is enriched in known composite motifs, predictive of binding site configurations in TF–TF–DNA crystal structures, and supported by ChIP-seq datasets. Structural modelling revealed three cooperativity mechanisms: direct protein–protein interactions, potentially indirect interactions and ‘through-DNA’ interactions. Indeed, 38% of the predicted complexes were found to contain four or more bases in which TF pairs appear to synergize through overlapping binding to the same DNA base pairs in opposite grooves or strands. Our TF complex and associated binding site predictions are available as a web resource at http://bejerano.stanford.edu/complex .

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Crystal Structure of PU.1/IRF-4/DNA Ternary Complex

Cited by 151 publications

References 39 publications

Variant IRF4/MUM1 associates with CD38 status and treatment-free survival in chronic lymphocytic leukaemia

Variant IRF4/MUM1 associates with CD38 status and treatment-free survival in chronic lymphocytic leukaemia

Targeted Chemical Wedges Reveal the Role of Allosteric DNA Modulation in Protein−DNA Assembly

Structure-aided prediction of mammalian transcription factor complexes in conserved non-coding elements

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