Pathogenic and Non-pathogenic Polyglutamine Tracts Have Similar Structural Properties: Towards a Length-dependent Toxicity Gradient

Klein, Fabrice; Pastore, Annalisa; Masino, Laura; Zeder‐Lutz, Gabrielle; Nierengarten, Hélène; Oulad‐Abdelghani, Mustapha; Altschuh, Danièle; Mandel, Jean‐Louis; Trottier, Yvon

doi:10.1016/j.jmb.2007.05.028

Cited by 85 publications

(113 citation statements)

References 41 publications

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“…We sampled the SDS resistance of HttEx1Qn of different polyQ stretch lengths and saw differences between short and long polyQ stretches, as observed previously (48). Correspondingly, we observed a clear difference between the secondary structure content of fibrils formed by HttEx1Q25 and HttEx1Q48 as determined by FTIR, with the latter being richer in amyloid-like structures.…”

Section: Bs3-d0 Peptidessupporting

confidence: 66%

Molecular Interaction between the Chaperone Hsc70 and the N-terminal Flank of Huntingtin Exon 1 Modulates Aggregation

Monsellier

Redeker

Ruiz-Arlandis

et al. 2015

Journal of Biological Chemistry

106

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Background: Hsc70 has an alleviating effect on the toxicity of polyglutamine (polyQ)-containing proteins in vivo. Results: Hsc70 binds specifically the N-terminal flank of huntingtin exon 1. Conclusion: Hsc70 interaction with huntingtin exon 1 N-terminal flank affects the conformation of the resulting assemblies. Significance: We identify the surface interfaces between Hsc70 and huntingtin exon 1, which allows the design of future therapeutic tools.

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Section: Bs3-d0 Peptidessupporting

confidence: 66%

Molecular Interaction between the Chaperone Hsc70 and the N-terminal Flank of Huntingtin Exon 1 Modulates Aggregation

Monsellier

Redeker

Ruiz-Arlandis

et al. 2015

Journal of Biological Chemistry

106

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“…Glutamine is a hydrophilic amino acid; therefore, the surface hydrophobicity of polyQ would not increase during early aggregation stages. In addition, the polyQ region is thought to be in a condensed disordered state in the native ensemble (33,34), therefore decreasing the accessibility of the side chains to sHsp interactions (35). In a manner akin to our findings with sHsps, molecular chaperones from other classes, e.g., Hsp70 and the chaperonin TRiC, which recognize surface hydrophobic patches of amyloidogenic intermediates, only weakly associate with polyQ proteins (28,36).…”

supporting

confidence: 63%

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

Robertson

Headey

Saunders

et al. 2010

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

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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.fibrillogenesis | α-crystallin

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“…Next, we examine the suggestion made by other studies that simple polyQ peptides aggregate into fibrils without populating conformationally distinct intermediates (38,39). Two-dimensional IR kinetic studies further support this hypothesis.…”

Section: Discussionmentioning

confidence: 70%

Structural motif of polyglutamine amyloid fibrils discerned with mixed-isotope infrared spectroscopy

Buchanan

Carr

Fluitt

et al. 2014

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

115

145

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Polyglutamine (polyQ) sequences are found in a variety of proteins, and mutational expansion of the polyQ tract is associated with many neurodegenerative diseases. We study the amyloid fibril structure and aggregation kinetics of K 2 Q 24 K 2 W, a model polyQ sequence. Two structures have been proposed for amyloid fibrils formed by polyQ peptides. By forming fibrils composed of both 12 C and 13 C monomers, made possible by protein expression in Escherichia coli, we can restrict vibrational delocalization to measure 2D IR spectra of individual monomers within the fibrils. The spectra are consistent with a β-turn structure in which each monomer forms an antiparallel hairpin and donates two strands to a single β-sheet. Calculated spectra from atomistic molecular-dynamics simulations of the two proposed structures confirm the assignment. No spectroscopically distinct intermediates are observed in rapid-scan 2D IR kinetics measurements, suggesting that aggregation is highly cooperative. Although 2D IR spectroscopy has advantages over linear techniques, the isotope-mixing strategy will also be useful with standard Fourier transform IR spectroscopy.Huntington disease | isotope dilution | antiparallel β-sheets | two-dimensional infrared spectroscopy N umerous neurodegenerative diseases, including Huntington disease, are associated with the mutational expansion of CAG repeats in specific genes. This expansion causes an increase in the length of normally benign polyglutamine (polyQ) tracts in expressed proteins (1, 2). In vivo, polyQ tracts occur embedded within larger proteins, such as the huntingtin protein. Full length proteins are impractical for detailed structural studies, and so isolated polyQ sequences are often used instead in experiments and simulations (3-5). Although isolated polyQ sequences may not aggregate in precisely the same manner as they would in fulllength proteins (3, 6, 7), it has been established that such models yield data that are relevant to some, if not all, polyQ pathologies (8). Additionally, proteolytic polyQ-containing fragments, rather than full-length proteins, may be the primary toxic species in Huntington disease (9) and some types of spinocerebellar ataxia (10). As a consequence, simple polyQ peptides remain an attractive alternative to more complicated proteins for understanding polyQmediated aggregation.A plethora of structures have been suggested for polyQ aggregates, ranging from α-helical coiled coils (11) or β-helices (12) to amyloid fibrils comprising stacked, linear β-sheets (13). Current consensus favors fibrillar structures, but the precise arrangement of the peptides within the fibril remains unclear. Most amyloid proteins form parallel β-sheets within fibrils, although antiparallel sheets do occur (14). Parallel sheets have been observed for glutamine-rich hexapeptides (15), but NMR studies (16), as well as the results presented here, suggest that sequences approaching the pathological length of 40 glutamines adopt an antiparallel structure. Fig. 1 shows two models that hav...

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Pathogenic and Non-pathogenic Polyglutamine Tracts Have Similar Structural Properties: Towards a Length-dependent Toxicity Gradient

Cited by 85 publications

References 41 publications

Molecular Interaction between the Chaperone Hsc70 and the N-terminal Flank of Huntingtin Exon 1 Modulates Aggregation

Molecular Interaction between the Chaperone Hsc70 and the N-terminal Flank of Huntingtin Exon 1 Modulates Aggregation

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

Structural motif of polyglutamine amyloid fibrils discerned with mixed-isotope infrared spectroscopy

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