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

Robertson A.L.; Headey S.J.; Saunders H.M.Ecroyd H.Scanlon M.J.Carver J.A.Bottomley S.P.

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

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

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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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2010年第23期|10424-10429|共6页
作者
Robertson A.L.; Headey S.J.; Saunders H.M.Ecroyd H.Scanlon M.J.Carver J.A.Bottomley S.P.;
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作者单位

Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia;

Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia;

School of Biological Sciences, University of Wollongong, Wollongong, NSW 2522, AustraliaSchool of Chemistry and Physics, University of Adelaide, Adelaide, SA 5005, Australia;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
α-crystallin; Fibrillogenesis;

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

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