Peptide Models for Inherited Neurodegenerative Disorders: Conformation and Aggregation Properties of Long Polyglutamine Peptides With and Without Interruptions (original) (raw)
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Molecular origin of polyglutamine aggregation in neurodegenerative diseases
PLoS Computational Biology, 2005
Expansion of polyglutamine (polyQ) tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases. Disease age of onset is correlated with the polyQ insert length above a critical value of 35-40 glutamines. The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence. While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood. Here, using computer simulations of isolated polyQ peptides, we show that a mechanism of aggregation is the conformational transition in a single polyQ peptide chain from random coil to a parallel b-helix. This transition occurs selectively in peptides longer than 37 glutamines. In the b-helices observed in simulations, all residues adopt b-strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 6 2 residues per turn. We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel b-hairpins in their ground state, in agreement with experiments. The lower stability of mutant b-helices explains their lower aggregation rates compared to wild type. Our results provide a molecular mechanism for polyQ-mediated aggregation. Citation: Khare SD, Ding F, Gwanmesia KN, Dokholyan NV (2005) Molecular origin of polyglutamine aggregation in neurodegenerative diseases. PLoS Comp Biol 1(3): e30.
Protein Science, 2003
Polyglutamine expansions, leading to aggregation, have been implicated in various neurodegenerative disorders. The range of repeats observed in normal individuals in most of these diseases is 19-36, whereas mutant proteins carry 40-81 repeats. In one such disorder, spinocerebellar ataxia (SCA1), it has been reported that certain individuals with expanded polyglutamine repeats in the disease range (Q 12 HQHQ 12 HQHQ 14/15 ) but with histidine interruptions were found to be phenotypically normal. To establish the role of histidine, a comparative study of conformational properties of model peptide sequences with (Q 12 HQHQ 12 HQHQ 12 ) and without (Q 42 ) interruptions is presented here. Q 12 HQHQ 12 HQHQ 12 displays greater solubility and lesser aggregation propensity compared to uninterrupted Q 42 as well as much shorter Q 22 . The solvent and temperature-driven conformational transitions ( structure ↔ random coil → ␣ helix) displayed by these model polyQ stretches is also discussed in the present report. The study strengthens our earlier hypothesis of the importance of histidine interruptions in mitigating the pathogenicity of expanded polyglutamine tract at the SCA1 locus. The relatively lower propensity for aggregation observed in case of histidine interrupted stretches even in the disease range suggests that at a very low concentration, the protein aggregation in normal cells, is possibly not initiated at all or the disease onset is significantly delayed. Our present study also reveals that besides histidine interruption, proline interruption in polyglutamine stretches can lower their aggregation propensity.
Random coil conformation for extended polyglutamine stretches in aqueous soluble monomeric peptides
Journal of Peptide Research, 2009
Several neurodegenerative diseases have been found to be strongly associated with proteins containing a polyglutamine stretch which is greatly expanded from approximately 20 glutamines in normal individuals to more than 40 in affected individuals. A conformational change in the expanded polyglutamine stretch has been suggested to form the molecular basis for disease onset. Model peptides containing polyglutamine tend to aggregate and become insoluble. We have synthesized readily water-soluble monomeric peptides by flanking polyglutamine stretches with sequences rich in alanine and lysine. Circular dichroism measurements show that polyglutamine stretches of length 9 or 17 adopt a random coil configuration in aqueous solution. We think that in the disease-associated peptides for normal individuals the stretches of-20 glutamines are in a random coil conformation, whereas in affected individuals the polyglutamine stretch may be in some other conformation. Our method to design soluble monomeric peptides containing extended polyglutamine stretches may be generally useful in studying other highly aggregating peptides. 0 Munksgaard 1997.
Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease
Biochemistry, 2017
Several hereditary neurological and neuromuscular diseases are caused by an abnormal expansion of trinucleotide repeats. To date, there have been ten of these trinucleotide repeat disorders associated with an expansion of the codon CAG encoding glutamine (Q). For these polyglutamine (polyQ) diseases, there is a critical threshold length of the CAG repeat required for disease, and further expansion beyond this threshold is correlated with age of onset and symptom severity. PolyQ expansion in the translated proteins promotes their self-assembly into a variety of oligomeric and fibrillar aggregate species that accumulate into the hallmark proteinaceous inclusion bodies associated with each disease. Here, we review aggregation mechanisms of proteins with expanded polyQ-tracts, structural consequences of expanded polyQ ranging from monomers to fibrillar aggregates, the impact of protein context and post translational modifications on aggregation, and a potential role for lipids membranes in aggregation. As the pathogenic mechanisms that underlie these disorders are often classified as either a gain of toxic function or loss of normal protein function, some toxic mechanisms associated with mutant polyQ tracts will also be discussed.
Oligoproline Effects on Polyglutamine Conformation and Aggregation
Journal of Molecular Biology, 2006
There are nine known expanded CAG repeat neurological diseases, including Huntington's disease (HD), each involving the repeat expansion of polyglutamine (polyGln) in a different protein. Similar conditions can be induced in animal models by expression of the polyGln sequence alone or in other protein contexts. Besides the polyGln sequence, the cellular context of the disease protein, and the sequence context of the polyGln within the disease protein, are both likely to contribute to polyGln physical behavior and to pathology. In HD, the N-terminal, exon-1 segment of the protein huntingtin contains the polyGln sequence immediately followed by an oligoproline region. We show here that introduction of a P 10 sequence Cterminal to polyGln in synthetic peptides decreases both the rate of formation and the apparent stability of the amyloid-like aggregates associated with this family of diseases. The sequence can be trimmed to P 6 without altering the suppression, but a P 3 sequence is ineffective. Spacers up to at least three amino acid residues in length can be inserted between polyGln and P 10 without altering this effect. There is no suppression, however, when the P 10 sequence is either placed on the Nterminal side of polyGln or attached to polyGln via a side-chain tether. The nucleation mechanism of a Q 40 sequence is unchanged upon addition of a P 10 C-terminal extension, yielding a critical nucleus of one. The effects of oligoPro length and structural context on polyGln aggregation are correlated strongly with alterations in the circular dichroism spectra of the monomeric peptides. For example, the P 10 sequence eliminates the small amount of alpha helical content otherwise exhibited by the Q 40 sequence. The P 10 sequence may suppress aggregation by stabilizing an aggregation-incompetent conformation of the monomer. The effect is transportable: a P 10 sequence fixed to the C terminus of the sequence Ab similarly modulates amyloid fibril formation.
FEBS Journal, 2008
The toxic aggregate hypothesis in polyglutamine diseases With the identification of expanded CAG repeats of the X-linked spinal and bulbar muscular atrophy (SBMA or Kennedy's disease) gene at the androgen receptor in 1991 [1], followed by the Huntington's disease (HD) gene in 1993 [2], and the cloning of the spinocerebellar ataxia type 1 gene [3], the expanded polyglutamine tract as the result of a CAG DNA expansion became the focus of intense interest to investigators in these diseases. Two seminal papers appeared near that time that presented hypotheses concerning the pathogenic mechanism of polyglutamine expansion. One was from Nobel laureate Max Perutz, demonstrating the concept of polyglutamine 'polar zipper' interactions with the side groups of glutamine residues [4]. Perutz focused on the fact that the genetics of some (but not all) polyglutamine diseases demonstrated that the minimal length of polyglutamine expansion required for disease was 37 repeats, and that a repeat length beyond 37 led to earlier disease onset. That paper demonstrated that polyglutamine alone was toxic to Escherichia coli and Chinese hamster ovary cells, and concluded that polyglutamine had the ability to adopt a pleated b-sheet structure that could cause a displacement of water molecules and hence render the protein insoluble. This theory was consistent with the genetic gain-of-function seen with mutant proteins in HD, in the ataxin-1 protein in spinocerebellar ataxia (SCA) type 1, and other polyglutamine diseases. Polar zippers were predicted to form tighter interactions with increasing polyglutamine length, thus potentially affecting the severity of disease.
Polyglutamine neurodegeneration: protein misfolding revisited
Trends in Neurosciences, 2008
Polyglutamine diseases are a major cause of neurodegenerative disease worldwide. Recent studies highlight the importance of protein quality control mechanisms in regulating polyglutamine-induced toxicity. Drawing on these studies, we propose a model of disease pathogenesis that integrates current understanding of the role of protein folding in polyglutamine disease. We also incorporate new findings on other age-related neurodegenerative diseases in an effort to explain how protein aggregation and normal aging processes might be involved in polyglutamine disease pathogenesis.
Journal of Biomolecular Structure and Dynamics, 2016
Spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) are two common autosomal-dominant inherited ataxia syndromes, both of which are related to the unstable expansion of tri-nucleotide CAG repeats in the coding region of the related ATXN2 and ATXN3 genes, respectively. The poly-glutamine (poly-Q) tract encoded by the CAG repeats has long been recognized as an important factor in disease pathogenesis and progress. In this study, using the I-TASSER method for 3D structure prediction, we investigated the effect of poly-Q tract enlargement on the structure and folding of ataxin-2 and ataxin-3 proteins. Our results show good agreement with the known experimental structures of the Josephin and UIM domains providing credence to the simulation results presented here, which show that the enlargement of the poly-Q region not only affects the local structure of these regions but also affects the structures of functional domains as well as the whole protein. The changes observed in the predicted models of the UIM domains in ataxin-3 when the poly-Q track is enlarged provide new insights on possible pathogenic mechanisms.