Structures of Heat Shock Factor Trimers Bound to DNA Reveal the Panoramic Architecture of the HSF-Regulated Transcriptional Machinery

Heat shock factor 1 (HSF1) and 2 (HSF2) play distinct but overlapping regulatory roles in maintaining cellular protein homeostasis or mediating cell differentiation anddevelopment. Upon activation, both HSFs trimerize and bind to heat shock elements(HSEs) present in the promoter region of target genes. Despite innovative insights gained from recent structural studies, the panoramic architecture of this transcriptional machinery remains to be determined. Here, we present crystal structures of humanHSF1 and HSF2 trimers bound to DNA, which reveal a triangular arrangement of thethree DNA-binding domains (DBDs) with protein-protein interactions largely mediated by the wing domain. Two structural properties, the different flexibility of the wing domain and local DNA conformational changes induced by HSF binding, seem likelyto contribute to the subtle differential specificity between HSF1 and HSF2. Besides, two more structures showing DBDs bound to ‘two-site’ head-to-head HSEs weredetermined as additions to the published tail-to-tail dimer-binding structures. Our structures lay a foundation for further mechanistic study on how HSFs fulfill complex regulation on different target genes.