Heat shock proteins (hsps) are rapidly produced at high levels in response to stress. They function in the cell to aid in proper protein folding and translocation and to prevent inappropriate protein aggregation. The accumulation of misfolded proteins is central to diseases of protein folding, including sickle cell haemoglobin, cystic fibrosis and prion diseases, in addition to multifactorial diseases such as bacterial and viral infections, myocardial ischaemia, neurodegenerative diseases and cancer. Heat shock factor 1 (HSF1) is the major stress-responsive transcriptional activator of heat shock proteins. Heat shock binding protein 1 (HSBP1) interacts with HSF1 and negatively regulates its activity through an unknown mechanism. The interaction between HSF1 and HSBP1 negatively regulates HSF1 transcriptional activity. This association mediates a change in at least one step of the multiphase process of HSF1 activation and attenuation. The proposed research plan is to determine the mechanism of HSBP1 regulation of HSF1 activity. By the overexpression of HSBP1 and the expression of a dominant negative mutant of HSBP1, the affect of HSBP1 on individual characteristics of HSF1 activation/attenuation will be determined. In addition, the structure/function relationship of HSBP1 will be investigated by random mutagenesis studies. We also propose determining the temporal and spatial relationship of the HSBP1 regulation of HSF1 in order to propose a model for the regulation of protein homeostasis during the cellular stress response.
| Tai, Li-Jung; McFall, Sally M; Huang, Kai et al. (2002) Structure-function analysis of the heat shock factor-binding protein reveals a protein composed solely of a highly conserved and dynamic coiled-coil trimerization domain. J Biol Chem 277:735-45 |
