A Model for Small Heat Shock Protein Inhibition of Polyglutamine Aggregation
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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.
KeywordsαB-crystallin Small heat shock proteins SHsp Ataxin-3 PolyQ Spinocerebellar ataxia Fibrillar aggregation
The authors EFH and CL are grateful to the Welch Foundation (Grant # BH-0018) for its continuing support of the Chemistry Department at St. Edward’s University. We thank Dr. Arthur Olson for the AutoDock 4.0 and AutoGrid 4.0 programs. This paper is dedicated to the memory of Woody Guthrie, who on October 3, 1967 died from complications of Huntington’s disease.
- 11.Robertson, A. L., Headeyb, S. J., Saunders, H. M., Ecroyd, H., Scanlon, H. M., Carver, J. A., et al. (2010). Small heat-shock proteins interact with a flanking domain to suppress polyglutamine aggregation. Proceedings of the National Academy of Sciences of the USA, 107, 10424–10429.PubMedCentralPubMedCrossRefGoogle Scholar
- 22.Nicastro, G., Menon, R. P., Masino, L., Knowles, P. P., McDonald, N. Q., & Pastore, A. (2005). The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition. Proceedings of the National Academy of Sciences of the USA, 102, 10493–10498.PubMedCentralPubMedCrossRefGoogle Scholar
- 26.AutoDock Tools [http://autodock.scripps.edu/resources/adt/index_html].