title: Structures of HSF2 reveal mechanisms for differential regulation of human heat-shock factors.
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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Jaeger
authors.affiliation: Duke University Human Vaccine Institute Macromolecular Crystallography Center, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Pemble
authors.affiliation: Department of Biosciences, Åbo Akademi University, Turku, Finland.
authors.forename: Lea
authors.identifier: http://orcid.org/0000-0003-1341-2867
authors.initials: L
authors.lastname: Sistonen
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Thiele
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D058207:Sumoylation; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D014157:Transcription Factors; C070389:HSF2 protein, human; D004247:DNA