Structures of HSF2 reveal mechanisms for differential regulation of human heat-shock factors

Alex M Jaeger, Charles W Pemble, Lea Sistonen, Dennis J Thiele

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Heat-shock transcription factor (HSF) family members function in stress protection and in human diseases including proteopathies, neurodegeneration and cancer. The mechanisms that drive distinct post-translational modifications, cofactor recruitment and target-gene activation for specific HSF paralogs are unknown. We present crystal structures of the human HSF2 DNA-binding domain (DBD) bound to DNA, revealing an unprecedented view of HSFs that provides insights into their unique biology. The HSF2 DBD structures resolve a new C-terminal helix that directs wrapping of the coiled-coil domain around DNA, thereby exposing paralog-specific sequences of the DBD surface for differential post-translational modifications and cofactor interactions. We further demonstrate a direct interaction between HSF1 and HSF2 through their coiled-coil domains. Together, these features provide a new model for HSF structure as the basis for differential and combinatorial regulation, which influences the transcriptional response to cellular stress.

Original languageEnglish
Pages (from-to)147-54
Number of pages8
JournalNature structural & molecular biology
Volume23
Issue number2
DOIs
Publication statusPublished - Feb 2016
MoE publication typeA1 Journal article-refereed

Keywords

  • Amino Acid Sequence
  • Base Sequence
  • Crystallography, X-Ray
  • DNA/chemistry
  • DNA-Binding Proteins/chemistry
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins/chemistry
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Sumoylation
  • Transcription Factors/chemistry

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