The transcription factor ICP4 from herpes simplex\nvirus has a central role in regulating the gene expression\ncascade which controls viral infection. Here\nwe present the crystal structure of the functionally\nessential ICP4 DNA binding domain in complex\nwith a segment from its own promoter, revealing a\nnovel homo-dimeric fold. We also studied the complex\nin solution by small angle X-Ray scattering, nuclear\nmagnetic resonance and surface-plasmon resonance\nwhich indicated that, in addition to the globular\ndomain, a flanking intrinsically disordered region\nalso recognizes DNA. Together the data provides a\nrationale for the bi-partite nature of the ICP4 DNA\nrecognition consensus sequence as the globular and\ndisordered regions bind synergistically to adjacent\nDNA motifs. Therefore in common with its eukaryotic\nhost, the viral transcription factor ICP4 utilizes\ndisordered regions to enhance the affinity and tune\nthe specificity of DNA interactions in tandem with a\nglobular domain.
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