Abstract
The transcription factor ICP4 from herpes simplex virus has a central role in regulating the gene expression cascade which controls viral infection. Here we present the crystal structure of the functionally essential ICP4 DNA binding domain in complex with a segment from its own promoter, revealing a novel homo-dimeric fold. We also studied the complex in solution by small angle X-Ray scattering, nuclear magnetic resonance and surface-plasmon resonance which indicated that, in addition to the globular domain, a flanking intrinsically disordered region also recognizes DNA. Together the data provides a rationale for the bi-partite nature of the ICP4 DNA recognition consensus sequence as the globular and disordered regions bind synergistically to adjacent DNA motifs. Therefore in common with its eukaryotic host, the viral transcription factor ICP4 utilizes disordered regions to enhance the affinity and tune the specificity of DNA interactions in tandem with a globular domain.
Highlights
Herpes simplex virus-1 (HSV-1) causes lifelong infections, typified by the sporadic appearance of acute localized symptoms such as cold sores, inter-dispersed by prolonged asymptomatic periods where the virus remains in a latent state
infected cell protein 4 (ICP4) interacts with numerous sites within the HSV genome, with affinity highest for viral DNA fitting the bi-partite consensus sequence RTCGTCNNYNYSG, it can interact with non-consensus sites, a property which may contribute to its transactivation function [29,30,31]
Due to the essential functional role of the DNA binding domain of ICP4, we have characterized the structure of this region revealing the details for sequence-specific DNA recognition and the data allowing us to consider how ICP4 can bind to alterative sequences
Summary
Herpes simplex virus-1 (HSV-1) causes lifelong infections, typified by the sporadic appearance of acute localized symptoms such as cold sores, inter-dispersed by prolonged asymptomatic periods where the virus remains in a latent state. During herpes infection a sequential cascade of viral gene expression is triggered. ICP4 can induce the expression of E and L genes [8,9], while it can act as a repressor notably of itself and other IE genes [10,11,12]. It carries out these functions by interacting with DNA and modulating the activity of the cellular RNA polymerase II on viral genes [13,14,15,16]
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