Heat Shock Protein 70 and 90 Family in Prostate Cancer.

Prostate cancer (PCa) is the second most frequent cancer that affects aging men worldwide. However, its exact pathogenesis has not been fully elucidated. The heat shock protein (HSP) family has cell-protective properties that may promote tumor growth and protect cancer cells from death. On a cellular level, HSP molecules have a strong relationship with multiple important biological processes, such as cell differentiation, epithelial-mesenchymal transition (EMT), and fibrosis. Because of the facilitation of HSP family molecules on tumorigenesis, a number of agents and inhibitors are being developed with potent antitumor effects whose target site is the critical structure of HSP molecules. Among all target molecules, HSP70 family and HSP90 are two groups that have been well studied, and therefore, the development of their inhibitors makes great progress. Only a small number of agents, however, have been clinically tested in recruited patients. As a result, more clinical studies are warranted for the establishment of the relationship between the HSP70 family, alongside the HSP90 molecule, and prostate cancer treatment.

Homology modeling, ligand docking and in silico mutagenesis of neurospora Hsp80 (90): insight into intrinsic ATPase activity.

The Hsp90 family of proteins is an important component of the cellular response to elevated temperatures, environmental or physiological stress and nuclear receptor signalling. The primary object of this work is the 80-kDa heat shock protein, a member of the Hsp90 family, from the model filamentous fungus Neurospora crassa, (henceforth referred to as Hsp80Nc). In contrast to more extensively characterized members of the same family, (e.g. Hsp82Sc of Saccharomyces cerevisiae) it exhibits a higher intrinsic ATPase activity and the ability to form hetero-oligomeric complexes with Hsp70 in the absence of co-chaperones or other ancillary factors. As unabridged experimentally derived structures of Hsp80Nc or Hsp82Sc are not available; we developed homology-based models for both of them. A structural analysis and comparison of these models was undertaken to better understand the nature of dimerization-induced changes in secondary structure and patterns of residue interaction. Our studies yielded some interesting and novel insights into the synergistic and mutually reinforcing nature of interactions between major domains of the two chains in their dimeric forms. We also evaluated the effect of residue substitutions in the 'lid' region of Hsp80Nc and Hsp82Sc on the calculated ligand-binding energy of ATP (and ADP) to their respective N-terminal domains. Our studies suggest that the higher intrinsic ATPase activity of Hsp80Nc may be attributable to differences in the residue sequences between the lid region of these two proteins.