Structures of heat shock factor trimers bound to DNA

Na Feng,Han Feng,Sheng Wang,Avinash S Punekar,Rudolf Ladenstein,Da-Cheng Wang,Qinghua Zhang,Jingjin Ding,Wei Liu

doi:10.1016/j.isci.2021.102951

Abstract

SummaryHeat shock factor 1 (HSF1) and 2 (HSF2) play distinct but overlapping regulatory roles in maintaining cellular proteostasis or mediating cell differentiation and development. Upon activation, both HSFs trimerize and bind to heat shock elements (HSEs) present in the promoter region of target genes. Despite structural insights gained from recent studies, structures reflecting the physiological architecture of this transcriptional machinery remains to be determined. Here, we present co-crystal structures of human HSF1 and HSF2 trimers bound to DNA, which reveal a triangular arrangement of the three DNA-binding domains (DBDs) with protein-protein interactions largely mediated by the wing domain. Two structural properties, different flexibility of the wing domain and local DNA conformational changes induced by HSF binding, seem likely to contribute to the subtle differential specificity between HSF1 and HSF2. Besides, two more structures showing DBDs bound to “two-site” head-to-head HSEs were determined as additions to the published tail-to-tail dimer-binding structures.

Highlights

All living cells and tissues are constantly challenged by acute or chronic stress
heat shock proteins (HSPs) expression is regulated at the transcriptional level through cis-acting nucleotide sequences called heat shock elements (HSEs), which are multiply present in the promoter region of heat shock genes (Akerfelt et al, 2010a; Bjork and Sistonen, 2010)
Structure of the DNA-binding domains (DBDs) bound to ‘‘two-site’’ head-to-head HSEs Previous biochemical studies have shown that Heat shock factor 1 (HSF1) and HSF2 bind to a two-site tail-to-tail HSE with higher affinity than to a head-to-head counterpart (Tateishi et al, 2009), but the structural basis for this difference is not well understood owing to the lack of head-to-head structures

Summary

Introduction

All living cells and tissues are constantly challenged by acute or chronic stress. Exposure to various proteindamaging stimuli, such as elevated temperature, heavy metals, toxins and hypoxia, and various pathologic conditions, such as cancer, ischemia, infections, and inflammation, induces cellular responses for protein homeostasis (proteostasis) maintenance. The TTC triplet and downstream GAA are often separated by a pyrimidine-purine dinucleotide, but the nucleotides preceding downstream TTC in a head-to-head arrangement are unrestrained (Figure S1A) (Akerfelt et al, 2010a). Despite all these wellcharacterized consensus elements, recent comprehensive ChIP-seq experiments have demonstrated that HSEs are highly diverse with variable primary sequences, lengths, and orientations of the nGAAn repeats in sequenced genomes (Guertin and Lis, 2010; Vihervaara et al, 2013)

Methods

Results

Discussion

Conclusion