Structural insights into a yeast prion illuminate nucleation and strain diversity

Krishnan, Rajaraman; Lindquist, Susan

doi:10.1038/nature03679

Cited by 449 publications

(709 citation statements)

References 51 publications

Supporting

Mentioning

664

Contrasting

Unclassified

Order By: Relevance

“…Disruption of the in vitro-made amyloid aggregates of Sup35pNM has been reported at similar GuHCl concentrations. 40 As seen previously for the in vitro-made amyloid fibers of Sup35pN, 13 in vivo prion aggregates of Sup35p from Pichia methanolica ,41 and also for the in vitro-made amyloid fibers of Ure2p, 15 the in vitro-made aggregates of Rnq1p-(132-405) were more resistant to proteinase K digestion than the soluble protein (Figure 4(c) . Thus, we aggregated a recombinant fragment of Rnq1p containing aa 132-405.…”

Section: Rnq1p-(132-405) Aggregates Have An Amyloid-like Stable Confosupporting

confidence: 66%

“Prion-proof” for [PIN+]: Infection with In Vitro-made Amyloid Aggregates of Rnq1p-(132–405) Induces [PIN+]

Patel

Liebman

2007

Journal of Molecular Biology

127

102

View full text Add to dashboard Cite

show abstract

Section: Rnq1p-(132-405) Aggregates Have An Amyloid-like Stable Confosupporting

confidence: 66%

“Prion-proof” for [PIN+]: Infection with In Vitro-made Amyloid Aggregates of Rnq1p-(132–405) Induces [PIN+]

Patel

Liebman

2007

Journal of Molecular Biology

127

102

View full text Add to dashboard Cite

show abstract

“…This apparent inconsistency of previous results regarding amyloid toxicity may result from the structural diversity of amyloid, as amyloid-forming protein often misfolds into multiple conformations and each conformation could exert distinct physiological effects (19,23). Previous reports indicate that the thermodynamic parameter of temperature can modulate protein folding and dynamics of amyloid-forming proteins, leading to different amyloid conformations (19,(32)(33)(34). Here we took advantages of this fact by making distinct thtt amyloids simply by polymerizing thtt protein at 4°C or 37°C.…”

Section: Discussionmentioning

confidence: 94%

Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity

Nekooki-Machida¹,

Kurosawa

Nukina

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

206

224

View full text Add to dashboard Cite

A hallmark of polyglutamine diseases, including Huntington disease (HD), is the formation of ␤-sheet-rich aggregates, called amyloid, of causative proteins with expanded polyglutamines. However, it has remained unclear whether the polyglutamine amyloid is a direct cause or simply a secondary manifestation of the pathology. Here we show that huntingtin-exon1 (thtt) with expanded polyglutamines remarkably misfolds into distinct amyloid conformations under different temperatures, such as 4°C and 37°C. The 4°C amyloid has loop/turn structures together with mostly ␤-sheets, including exposed polyglutamines, whereas the 37°C amyloid has more extended and buried ␤-sheets. By developing a method to efficiently introduce amyloid into mammalian cells, we found that the formation of the 4°C amyloid led to substantial toxicity, whereas the toxic effects of the 37°C amyloid were very small. Importantly, thtt amyloids in different brain regions of HD mice also had distinct conformations. The thermolabile thtt amyloid with loop/turn structures in the striatum showed higher toxicity, whereas the rigid thtt amyloid with more extended ␤-sheets in the hippocampus and cerebellum had only mild toxic effects. These studies show that the thtt protein with expanded polyglutamines can misfold into distinct amyloid conformations and, depending on the conformations, the amyloids can be either toxic or nontoxic. Thus, the amyloid conformation of thtt may be a critical determinant of cytotoxicity in HD.Huntington disease ͉ polyglutamine misfolding ͉ aggregation

show abstract

“…It is noteworthy that Krishnan and Lindquist [93] have challenged this view in their recent work on the aggregation of a yeast prion. The conclusion that aggregation is limited by homogeneous nucleation is made mainly on the presence of a discernible and long lag time for the growth of the large, insoluble, β-sheet-rich aggregates and the elimination of these lag times with seeding.…”

Section: Implications Of Theoretical Predictions For Kinetics Of Aggrmentioning

confidence: 99%

A polymer physics perspective on driving forces and mechanisms for protein aggregation

Pappu

Wang

Vitalis

et al. 2008

Archives of Biochemistry and Biophysics

156

172

View full text Add to dashboard Cite

Protein aggregation is a commonly occurring problem in biology. Cells have evolved stress-response mechanisms to cope with problems posed by protein aggregation. Yet, these quality control mechanisms are overwhelmed by chronic aggregation-related stress and the resultant consequences of aggregation become toxic to cells. As a result, a variety of systemic and neurodegenerative diseases are associated with various aspects of protein aggregation and rational approaches to either inhibit aggregation or manipulate the pathways to aggregation might lead to an alleviation of disease phenotypes. To develop such approaches, one needs a rigorous and quantitative understanding of protein aggregation. Much work has been done in this area. However, several unanswered questions linger, and these pertain primarily to the actual mechanism of aggregation as well as to the types of intermolecular associations and intramolecular fluctuations realized at low protein concentrations. It has been suggested that the concepts underlying protein aggregation are similar to those used to describe the aggregation of synthetic polymers. Following this suggestion, the relevant concepts of polymer aggregation are introduced. The focus is on explaining the driving forces for polymer aggregation and how these driving forces vary with chain length and solution conditions. It is widely accepted that protein aggregation is a nucleation-dependent process. This view is based mainly on the presence of long times for the accumulation of aggregates and the elimination of these lag times with "seeds". In this sense, protein aggregation is viewed as being analogous to the aggregation of colloidal particles. The theories for polymer aggregation reviewed in this work suggest an alternative mechanism for the origin of long lag times in protein aggregation. The proposed mechanism derives from the recognition that polymers have unique dynamics that distinguish them from other aggregation-prone systems such as colloidal particles.

show abstract

Structural insights into a yeast prion illuminate nucleation and strain diversity

Cited by 449 publications

References 51 publications

“Prion-proof” for [PIN+]: Infection with In Vitro-made Amyloid Aggregates of Rnq1p-(132–405) Induces [PIN+]

“Prion-proof” for [PIN+]: Infection with In Vitro-made Amyloid Aggregates of Rnq1p-(132–405) Induces [PIN+]

Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity

A polymer physics perspective on driving forces and mechanisms for protein aggregation

Contact Info

Product

Resources

About