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Small heat-shock proteins interact with a flanking domain to suppress polyglutamine aggregation

Journal Article


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Abstract


  • Small heat-shock proteins (sHsps) are molecular chaperones that play an important protective role against cellular protein misfolding by interacting with partially unfolded proteins on their off-folding pathway, preventing their aggregation. Polyglutamine (polyQ) repeat expansion leads to the formation of fibrillar protein aggregates and neuronal cell death in nine diseases, including Huntington disease and the spinocerebellar ataxias (SCAs). There is evidence that sHsps have a role in suppression of polyQ-induced neurodegeneration; for example, the sHsp alphaB-crystallin (αB-c) has been identified as a suppressor of SCA3 toxicity in a Drosophila model. However, the molecular mechanism for this suppression is unknown. In this study we tested the ability of αB-c to suppress the aggregation of a polyQ protein. We found that αB-c does not inhibit the formation of SDS-insoluble polyQ fibrils. We further tested the effect of αB-c on the aggregation of ataxin-3, a polyQ protein that aggregates via a two-stage aggregation mechanism. The first stage involves association of the N-terminal Josephin domain followed by polyQ-mediated interactions and the formation of SDS-resistant mature fibrils. Our data show that αB-c potently inhibits the first stage of ataxin-3 aggregation; however, the second polyQ-dependent stage can still proceed. By using NMR spectroscopy, we have determined that αB-c interacts with an extensive region on the surface of the Josephin domain. These data provide an example of a domain/region flanking an amyloidogenic sequence that has a critical role in modulating aggregation of a polypeptide and plays a role in the interaction with molecular chaperones to prevent this aggregation.

Authors


  •   Roberston, Amy L. (external author)
  •   Headey, Stephen J. (external author)
  •   Saunders, Helen M. (external author)
  •   Ecroyd, Heath
  •   Scanlon, Martin J. (external author)
  •   Carver, John A. (external author)
  •   Bottomley, Stephen P. (external author)

Publication Date


  • 2010

Citation


  • Roberston, A. L., Headey, S. J., Saunders, H. M., Ecroyd, H., Scanlon, M. J., Carver, J. A. & Bottomley, S. P. (2010). Small heat-shock proteins interact with a flanking domain to suppress polyglutamine aggregation. Proceedings of the National Academy of Sciences of USA, 107 (23), 10424-10429.

Scopus Eid


  • 2-s2.0-77953799932

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1524&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/485

Has Global Citation Frequency


Number Of Pages


  • 5

Start Page


  • 10424

End Page


  • 10429

Volume


  • 107

Issue


  • 23

Abstract


  • Small heat-shock proteins (sHsps) are molecular chaperones that play an important protective role against cellular protein misfolding by interacting with partially unfolded proteins on their off-folding pathway, preventing their aggregation. Polyglutamine (polyQ) repeat expansion leads to the formation of fibrillar protein aggregates and neuronal cell death in nine diseases, including Huntington disease and the spinocerebellar ataxias (SCAs). There is evidence that sHsps have a role in suppression of polyQ-induced neurodegeneration; for example, the sHsp alphaB-crystallin (αB-c) has been identified as a suppressor of SCA3 toxicity in a Drosophila model. However, the molecular mechanism for this suppression is unknown. In this study we tested the ability of αB-c to suppress the aggregation of a polyQ protein. We found that αB-c does not inhibit the formation of SDS-insoluble polyQ fibrils. We further tested the effect of αB-c on the aggregation of ataxin-3, a polyQ protein that aggregates via a two-stage aggregation mechanism. The first stage involves association of the N-terminal Josephin domain followed by polyQ-mediated interactions and the formation of SDS-resistant mature fibrils. Our data show that αB-c potently inhibits the first stage of ataxin-3 aggregation; however, the second polyQ-dependent stage can still proceed. By using NMR spectroscopy, we have determined that αB-c interacts with an extensive region on the surface of the Josephin domain. These data provide an example of a domain/region flanking an amyloidogenic sequence that has a critical role in modulating aggregation of a polypeptide and plays a role in the interaction with molecular chaperones to prevent this aggregation.

Authors


  •   Roberston, Amy L. (external author)
  •   Headey, Stephen J. (external author)
  •   Saunders, Helen M. (external author)
  •   Ecroyd, Heath
  •   Scanlon, Martin J. (external author)
  •   Carver, John A. (external author)
  •   Bottomley, Stephen P. (external author)

Publication Date


  • 2010

Citation


  • Roberston, A. L., Headey, S. J., Saunders, H. M., Ecroyd, H., Scanlon, M. J., Carver, J. A. & Bottomley, S. P. (2010). Small heat-shock proteins interact with a flanking domain to suppress polyglutamine aggregation. Proceedings of the National Academy of Sciences of USA, 107 (23), 10424-10429.

Scopus Eid


  • 2-s2.0-77953799932

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1524&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/485

Has Global Citation Frequency


Number Of Pages


  • 5

Start Page


  • 10424

End Page


  • 10429

Volume


  • 107

Issue


  • 23