Abstract
Heat shock response (HSR) is a ubiquitous cellular mechanism that copes with a variety of stresses. This response is mediated by a family of transcriptional activators, heat shock factors (HSFs), which are under tight regulation. HSF binding protein 1 (HSBP1) is a negative regulator of HSR and is reported to bind specifically with the active trimeric form of HSF1, thus inhibiting its activity. HSBP1 contains heptad-repeats in the primary sequence and was believed to stay in a trimer form in solution. We report the crystal structure of the trimerization domain of the M30I/L55P mutant of human HSBP1 at 1.8 A resolution. In this crystal form, the HSBP1 fragment of residues 6-53 forms a continuous, 11-turn long helix. The helix self-associates to form a parallel, symmetrical, triple coiled-coil helix bundle, which further assembles into a dimer of trimers in a head-to-head fashion. Solution study confirmed that the wild-type HSBP1 shares similar biophysical properties with the crystallized variant. Furthermore, we identified Ser31, which buried its polar side chain in the hydrophobic interior of the helix bundle, as a stability weak-spot. Substitution of this residue with Ile increases the melting temperature by 24 degrees C, implicating that this conserved serine residue is maintained at position 31 for functional purposes.
Published Version
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