Effects of the enlargement of polyglutamine segments on the structure and folding of ataxin-2 and ataxin-3 proteins.
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ABSTRACT:
SUBMITTER: Wen J
PROVIDER: S-EPMC5580338 | biostudies-literature | 2017 Feb
REPOSITORIES: biostudies-literature
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Project description:The pathogenesis of spinocerebellar ataxia type 7 and other neurodegenerative polyglutamine (polyQ) disorders correlates with the aberrant accumulation of toxic polyQ-expanded proteins in the nucleus. Promyelocytic leukemia protein (PML) nuclear bodies are often present in polyQ aggregates, but their relation to pathogenesis is unclear. We show that expression of PML isoform IV leads to the formation of distinct nuclear bodies enriched in components of the ubiquitin-proteasome system. These bodies recruit soluble mutant ataxin-7 and promote its degradation by proteasome-dependent proteolysis, thus preventing the aggregate formation. Inversely, disruption of the endogenous nuclear bodies with cadmium increases the nuclear accumulation and aggregation of mutant ataxin-7, demonstrating their role in ataxin-7 turnover. Interestingly, beta-interferon treatment, which induces the expression of endogenous PML IV, prevents the accumulation of transiently expressed mutant ataxin-7 without affecting the level of the endogenous wild-type protein. Therefore, clastosomes represent a potential therapeutic target for preventing polyQ disorders.
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Project description:The homotrimeric fusion protein nucleocapsid (NC)-dUTPase combines domains that participate in RNA/DNA folding, reverse transcription, and DNA repair in Mason-Pfizer monkey betaretrovirus infected cells. The structural organization of the fusion protein remained obscured by the N- and C-terminal flexible segments of dUTPase and the linker region connecting the two domains that are invisible in electron density maps. Small-angle X-ray scattering reveals that upon oligonucleotide binding the NC domains adopt the trimeric symmetry of dUTPase. High-resolution X-ray structures together with molecular modeling indicate that fusion with NC domains dramatically alters the conformation of the flexible C-terminus by perturbing the orientation of a critical beta-strand. Consequently, the C-terminal segment is capable of double backing upon the active site of its own monomer and stabilized by non-covalent interactions formed with the N-terminal segment. This co-folding of the dUTPase terminal segments, not observable in other homologous enzymes, is due to the presence of the fused NC domain. Structural and genomic advantages of fusing the NC domain to a shortened dUTPase in betaretroviruses and the possible physiological consequences are envisaged.
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Project description:BackgroundThe expansion of polyglutamine (poly-Q) repeats in several unrelated proteins is associated with at least ten neurodegenerative diseases. The length of the poly-Q regions plays an important role in the progression of the diseases. The number of glutamines (Q) is inversely related to the onset age of these polyglutamine diseases, and the expansion of poly-Q repeats has been associated with protein misfolding. However, very little is known about the structural changes induced by the expansion of the repeats. Computational methods can provide an alternative to determine the structure of these poly-Q proteins, but it is important to evaluate their performance before large scale prediction work is done.ResultsIn this paper, two popular protein structure prediction programs, I-TASSER and Rosetta, have been used to predict the structure of the N-terminal fragment of a protein associated with Huntington's disease with 17 glutamines. Results show that both programs have the ability to find the native structures, but I-TASSER performs better for the overall task.ConclusionsBoth I-TASSER and Rosetta can be used for structure prediction of proteins with poly-Q repeats. Knowledge of poly-Q structure may significantly contribute to development of therapeutic strategies for poly-Q diseases.
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Project description:Expansion of the polyglutamine (polyQ) tract in the huntingtin (Htt) protein causes Huntington's disease (HD), a fatal inherited movement disorder linked to neurodegeneration in the striatum and cortex. S-nitrosylation and S-acylation of cysteine residues regulate many functions of cytosolic proteins. We therefore used a resin-assisted capture approach to identify these modifications in Htt. In contrast to many proteins that have only a single S-nitrosylation or S-acylation site, we identified sites along much of the length of Htt. Moreover, analysis of cells expressing full-length Htt or a large N-terminal fragment of Htt shows that polyQ expansion strongly increases Htt S-nitrosylation. This effect appears to be general since it is also observed in Ataxin-1, which causes spinocerebellar ataxia type 1 (SCA1) when its polyQ tract is expanded. Overexpression of nitric oxide synthase increases the S-nitrosylation of normal Htt and the frequency of conspicuous juxtanuclear inclusions of Htt N-terminal fragments in transfected cells. Taken together with the evidence that S-nitrosylation of Htt is widespread and parallels polyQ expansion, these subcellular changes show that S-nitrosylation affects the biology of this protein in vivo.
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Project description:Spinocerebellar ataxia type 1 (SCA1) is one of a group of nine expanded CAG repeat diseases, in which polyglutamine (polyQ) expansion above a threshold is associated with increased disease risk and aggregation. SCA1 is unique in which the polyQ in the disease protein, ataxin1, often contains a few His residues that appear to block toxicity. Here, we ask how His insertions affect aggregation by comparing a Q(30) peptide with and without a centrally inserted His-Gln-His sequence. We found that at pH 7.5-8.5, His interruptions decrease polyQ aggregation rates but do not change the spontaneous growth mechanism: nucleated growth polymerization with a critical nucleus of one without non-fibrillar intermediates. The decreased aggregation rates are because of reductions in nucleation equilibrium constants. At pH 6, however, the His-interrupted peptide aggregates by a different mechanism that involves a low ThT-binding intermediate and produces a polymorphic amyloid product. In aggregates grown at pH 7.5, the His residues are solvent-accessible. Aggregates of His-inserted polyQ are good seeds for Q(30) elongation, suggesting the potential to recruit polyQ proteins in the cell. Our data are therefore most consistent with His insertions blocking toxicity by suppressing rates and/or altering pathways of spontaneous aggregation.
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Project description:BACKGROUND: While some studies have shown that the 3D protein structures are more conservative than their amino acid sequences, other experimental studies have shown that even if two proteins share the same topology, they may have different folding pathways. There are many studies investigating this issue with molecular dynamics or Go-like model simulations, however, one should be able to obtain the same information by analyzing the proteins' amino acid sequences, if the sequences contain all the information about the 3D structures. In this study, we use information about protein sequences to predict the location of their folding segments. We focus on proteins with a ferredoxin-like fold, which has a characteristic topology. Some of these proteins have different folding segments. RESULTS: Despite the simplicity of our methods, we are able to correctly determine the experimentally identified folding segments by predicting the location of the compact regions considered to play an important role in structural formation. We also apply our sequence analyses to some homologues of each protein and confirm that there are highly conserved folding segments despite the homologues' sequence diversity. These homologues have similar folding segments even though the homology of two proteins' sequences is not so high. CONCLUSION: Our analyses have proven useful for investigating the common or different folding features of the proteins studied.
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Project description:Protein misfolding and aggregation is a pathogenic feature shared among at least ten polyglutamine (polyQ) neurodegenerative diseases. While solvent-solution interaction is a key factor driving protein folding and aggregation, the solvation properties of expanded polyQ tracts are not well understood. By using GPU-enabled all-atom molecular dynamics simulations of polyQ monomers in an explicit solvent environment, this study shows that solvent-polyQ interaction propensity decreases as the lengths of polyQ tract increases. This study finds a predominance in long-distance interactions between residues far apart in polyQ sequences with longer polyQ segments, that leads to significant conformational differences. This study also indicates that large loops, comprised of parallel ?-structures, appear in long polyQ tracts and present new aggregation building blocks with aggregation driven by long-distance intra-polyQ interactions. Finally, consistent with previous observations using coarse-grain simulations, this study demonstrates that there is a gain in the aggregation propensity with increased polyQ length, and that this gain is correlated with decreasing ability of solvent-polyQ interaction. These results suggest the modulation of solvent-polyQ interactions as a possible therapeutic strategy for treating polyQ diseases.
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Project description:Spinocerebellar ataxia type 7 (SCA7) is characterized by cone-rod dystrophy retinal degeneration and is caused by a polyglutamine [poly(Q)] expansion within ataxin-7, a protein of previously unknown function. Here, we report that ataxin-7 is an integral component of the mammalian STAGA (SPT3-TAF9-ADA-GCN5 acetyltransferase) transcription coactivator complex, interacts directly with the GCN5 histone acetyltransferase component of STAGA, and mediates a direct interaction of STAGA with the CRX (cone-rod homeobox) transactivator of photoreceptor genes. Consistent with these results, chromatin immunoprecipitation assays document retinal-specific association of CRX, GCN5, and acetylated histone H3 with CRX target genes. RNA interference studies also implicate ataxin-7 and GCN5 in CRX-dependent gene activation, and histone deacetylase inhibitors restore the compromised expression of a CRX target gene in an ataxin-7-deficient background. Significantly, in relation to SCA7, poly(Q)-expanded ataxin-7 gets incorporated into STAGA and, in a dominant-negative manner, inhibits the nucleosomal histone acetylation function of STAGA GCN5 both in vitro and, based on chromatin immunoprecipitation assays, in SCA7 transgenic mice. These results suggest that the normal function of a poly(Q) disease protein may intersect with its pathogenic mechanism, an observation with significant implications for the molecular basis of all poly(Q) disorders and ultimately for their treatment.
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Project description:The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27-33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43-ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.
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Project description:Spinocerebellar ataxia type 3 (SCA3) is a devastating neurodegenerative disease for which there is currently no cure, nor effective treatment strategy. One of nine polyglutamine disorders known to date, SCA3 is clinically heterogeneous and the main feature is progressive ataxia, which in turn affects speech, balance and gait of the affected individual. SCA3 is caused by an expanded polyglutamine tract in the ataxin-3 protein, resulting in conformational changes that lead to toxic gain of function. The expanded glutamine tract is located at the 5' end of the penultimate exon (exon 10) of ATXN3 gene transcript. Other studies reported removal of the expanded glutamine tract using splice switching antisense oligonucleotides. Here, we describe improved efficiency in the removal of the toxic polyglutamine tract of ataxin-3 in vitro using phosphorodiamidate morpholino oligomers, when compared to antisense oligonucleotides composed of 2'-O-methyl modified bases on a phosphorothioate backbone. Significant downregulation of both the expanded and non-expanded protein was induced by the morpholino antisense oligomer, with a greater proportion of ataxin-3 protein missing the polyglutamine tract. With growing concerns over toxicity associated with long-term administration of phosphorothioate oligonucleotides, the use of a phosphorodiamidate morpholino oligomer may be preferable for clinical application. These results suggest that morpholino oligomers may provide greater therapeutic benefit for the treatment of spinocerebellar ataxia type 3, without toxic effects.
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