β-Hairpin-Mediated Nucleation of Polyglutamine Amyloid Formation

JOURNAL OF MOLECULAR BIOLOGY

卷:425

Article

Kar, Karunakar^1,2  Hoop, Cody L.¹  Drombosky, Kenneth W.^1,2  Baker, Matthew A.³  Kodali, Ravindra^1,2  Arduini, Irene^1,2  van der Wel, Patrick C. A.¹  Horne, W. Seth³  Wetzel, Ronald^1,2 

[1] Univ Pittsburgh, Dept Biol Struct, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Sch Med, Pittsburgh, PA 15260 USA

[3] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA

关键词: amyloid;    nucleation;    structure;    polyglutamine;    kinetics;   

DOI  :  10.1016/j.jmb.2013.01.016

来源: Elsevier

【 摘 要 】

The conformational preferences of polyglutamine (polya) sequences are of major interest because of their central importance in the expanded CAG repeat diseases that include Huntington's disease. Here, we explore the response of various biophysical parameters to the introduction of beta-hairpin motifs within polya sequences. These motifs (tryptophan zipper, disulfide, D-Pro-Gly, Coulombic attraction, L-Pro-Gly) enhance formation rates and stabilities of annyloid fibrils with degrees of effectiveness well correlated with their known abilities to enhance beta-hairpin formation in other peptides. These changes led to decreases in the critical nucleus for amyloid formation from a value of n* = 4 for a simple, unbroken Q(23) sequence to approximate unitary n* values for similar length polyas containing beta-hairpin motifs. At the same time, the morphologies, secondary structures, and bioactivities of the resulting fibrils were essentially unchanged from simple polya aggregates. In particular, the signature pattern of solid-state NMR C-13 Gln resonances that appears to be unique to polya amyloid is replicated exactly in fibrils from a beta-hairpin polyQ. Importantly, while beta-hairpin motifs do produce enhancements in the equilibrium constant for nucleation in aggregation reactions, these icr values remain quite low (similar to 10(- 10)) and there is no evidence for significant enhancement of beta-structure within the monomer ensemble. The results indicate an important role for beta-turns in the nucleation mechanism and structure of polya amyloid and have implications for the nature of the toxic species in expanded CAG repeat diseases. (C) 2013 Elsevier Ltd. All rights reserved.

【 授权许可】

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