Download Capturing denaturing proteins * Small Heat Shock Protein substrate

Capturing denaturing proteins – Small Heat Shock Protein substrate recognition
Elizabeth Vierling and Indu Santhanagopalan
Protein aggregation resulting from stress, disease or mutation poses a major threat to all cells.
The ubiquitous small heat shock proteins (sHSPs) act as molecular chaperones to prevent
irreversible protein aggregation and are significant components of the protein quality control
network. Expression and/or mutation of sHSPs are linked to multiple diseases of protein
misfolding, including neurodegenerative diseases, myopathies and cataract. The mechanism of
sHSP chaperone action and interaction with substrates, therefore, has wide-ranging implications
for understanding cellular stress and disease processes. We are studying the mechanism of sHSP
substrate recognition by identifying specific crosslinking sites between sHSPs and denaturing
substrates. sHSPs are oligomeric proteins of 12 to > 24 subunits, which readily dissociate to
bind up to an equal weight of denaturing proteins. Substrates in these large, soluble and
heterogenous sHSP-substrate complexes are later released and refolded by ATP-dependent
chaperones. Pinpointing sHSP:substrate interaction sites, as well as determining the overall
organization of the these complexes, is critical to understanding how they carry out their
chaperone function.