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

Nat Struct Mol Biol. 2016 Feb;23(2):147-54. doi: 10.1038/nsmb.3150. Epub 2016 Jan 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • DNA-Binding Proteins
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins
  • Transcription Factors
  • HSF2 protein, human
  • DNA