Fate of Protein Damage in Mammalian Cells: Effects of Molecular Chaperones

摘要

Protein damage is believed to play a central role in the cell killing and radio- and drug-sensitising effects of hyperthermia. As a result of protein denaturation, exposure of hydrophobic groups and protein thiol groups gives rise to protein (HSPs) aggregates. These aggregates can accumulate throughout the cell and impair macromolecular structures and their associated processes. Heat-shock proteins have been implicated in protecting cells against the detrimental effects of hyperthermia. In accordance with their chaperone function described in cell-free systems, a role in the prevention and/or restoration of protein damage within the mammalian has been assumed. Indeed, evidence has been obtained that e.g. HSPs can protect cells against heat-induced protein denaturation and aggregation and/or accelerate protein disaggregation in intact cells. Much of this evidence has been based on activity or solubility measurements of "reporter" proteins. Singular measurements do not provide direct insight into the level of damage or allow for a precise insight in the protective mechanism of chaperones. Here, both theoretical and experimental information is provided on the extent of protein damage, the information one gets from combined activity and solubility measurements and the various stages at which HSP27 and HSP70 as chaperones may interfere with that damage.