A model for small heat shock protein inhibition of polyglutamine aggregation.
Polyglutamine (polyQ) repeat expansions that lead to the formation of amyloid aggregates are linked to several devastating neurodegenerative disorders. While molecular chaperones, including the small heat shock proteins (sHsp), play an important role in protection against protein misfolding, the aberrant protein folding that accompanies these polyQ diseases overwhelms the chaperone network. By generating a model structure to explain the observed suppression of spinocerebellar ataxia 3 (SCA3) by the sHsp αB-crystallin, we have identified key vulnerabilities that provide a possible mechanism to explain this heat shock response. A docking study involving a small bioactive peptide should also aid in the development of new drug targets for the prevention of polyQ-based aggregation.
Department of Chemistry, St. Edward's University, Austin, TX, 78704, USA, healy@stedwards.edu.
Eamonn F
EF
Healy
Carley
C
Little
Peter J
PJ
King
D000067699:Ataxin-3; D001665:Binding Sites; D030562:Databases, Protein; D050888:Heat-Shock Proteins, Small / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000737:chemistry / Q000378:metabolism
D050888:Heat-Shock Proteins, Small; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D038203:alpha-Crystallin B Chain; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3