Characterization of the <scp>AXH</scp> domain of Ataxin‐1 using enhanced sampling and functional mode analysis

Deriu, Marco Agostino; Grasso, Gianvito; Tuszyński, Jack A.; Massai, Diana Nada Caterina; Gallo, Diego; Morbiducci, Umberto; Danani, Andrea

doi:10.1002/prot.25017

Cited by 21 publications

(35 citation statements)

References 35 publications

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“…The JD residues mainly responsible for the interaction with TFE have been identified by contact probability plots [11]. The secondary structure of the protein has been calculated by the STRIDE software [54] on several snapshots along the simulation time at the conformational equilibrium, as done in previous studies [11,12,13,55,56]. Two descriptors were considered to identify the JD conformational properties: The JD Radius of Gyration (RG), and the hairpin angle, successfully employed in recent literature to describe the sampling of JD conformations [12,38].…”

Section: Methodsmentioning

confidence: 99%

Protein Environment: A Crucial Triggering Factor in Josephin Domain Aggregation: The Role of 2,2,2-Trifluoroethanol

Visentin

Navarro

Grasso

et al. 2018

IJMS

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The protein ataxin-3 contains a polyglutamine stretch that triggers amyloid aggregation when it is expanded beyond a critical threshold. This results in the onset of the spinocerebellar ataxia type 3. The protein consists of the globular N-terminal Josephin domain and a disordered C-terminal tail where the polyglutamine stretch is located. Expanded ataxin-3 aggregates via a two-stage mechanism: first, Josephin domain self-association, then polyQ fibrillation. This highlights the intrinsic amyloidogenic potential of Josephin domain. Therefore, much effort has been put into investigating its aggregation mechanism(s). A key issue regards the conformational requirements for triggering amyloid aggregation, as it is believed that, generally, misfolding should precede aggregation. Here, we have assayed the effect of 2,2,2-trifluoroethanol, a co-solvent capable of stabilizing secondary structures, especially α-helices. By combining biophysical methods and molecular dynamics, we demonstrated that both secondary and tertiary JD structures are virtually unchanged in the presence of up to 5% 2,2,2-trifluoroethanol. Despite the preservation of JD structure, 1% of 2,2,2-trifluoroethanol suffices to exacerbate the intrinsic aggregation propensity of this domain, by slightly decreasing its conformational stability. These results indicate that in the case of JD, conformational fluctuations might suffice to promote a transition towards an aggregated state without the need for extensive unfolding, and highlights the important role played by the environment on the aggregation of this globular domain.

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Section: Methodsmentioning

confidence: 99%

Protein Environment: A Crucial Triggering Factor in Josephin Domain Aggregation: The Role of 2,2,2-Trifluoroethanol

Visentin

Navarro

Grasso

et al. 2018

IJMS

Self Cite

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“…The AXH domain is responsible for transcriptional repression, RNA-binding activity, and is necessary for interacting with other proteins, mostly transcriptional regulators. For the domain to be able to bind all its different substrates, it has a remarkable conformational plasticity (Chen et al, 2004; De Chiara et al, 2013b; Deriu et al, 2016). Moreover, the AXH domain is responsible for ATXN1 self-association.…”

Section: Binding Partners That Can Influence Aggregationmentioning

confidence: 99%

Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch

et al. 2017

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Expanded polyglutamine (polyQ) stretches in at least nine unrelated proteins lead to inherited neuronal dysfunction and degeneration. The expansion size in all diseases correlates with age at onset (AO) of disease and with polyQ protein aggregation, indicating that the expanded polyQ stretch is the main driving force for the disease onset. Interestingly, there is marked interpatient variability in expansion thresholds for a given disease. Between different polyQ diseases the repeat length vs. AO also indicates the existence of modulatory effects on aggregation of the upstream and downstream amino acid sequences flanking the Q expansion. This can be either due to intrinsic modulation of aggregation by the flanking regions, or due to differential interaction with other proteins, such as the components of the cellular protein quality control network. Indeed, several lines of evidence suggest that molecular chaperones have impact on the handling of different polyQ proteins. Here, we review factors differentially influencing polyQ aggregation: the Q-stretch itself, modulatory flanking sequences, interaction partners, cleavage of polyQ-containing proteins, and post-translational modifications, with a special focus on the role of molecular chaperones. By discussing typical examples of how these factors influence aggregation, we provide more insight on the variability of AO between different diseases as well as within the same polyQ disorder, on the molecular level.

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“…The evolutionary conserved 120 aa AXH domain that spans exon 8 and 9 is highly homologous to the large region of the high mobility group box transcription factor-binding protein 1 (HBP1) [90,91]. The AXH domain is known as a dimerization domain and is the only globular dimer forming region identified in the protein [92].…”

Section: Wild-type and Mutant Proteinmentioning

confidence: 99%

“…The AXH domain is known as a dimerization domain and is the only globular dimer forming region identified in the protein [92]. Additionally, the AXH folds independently into an oligonucleotide-binding fold, able to recognise RNA with a similar nucleotide preference, to that of full length ataxin-1 [91,93]. Second to RNA binding, the AXH domain contains a cluster of charged surface residues that allows for another secondary binding surface.…”

Section: Wild-type and Mutant Proteinmentioning

confidence: 99%

“…This leads to the several protein-protein interactions through the ataxin-1 AXH domain, namely a paralog of ataxin-1, brother of ataxin-1 (BOAT), which also contains a AXH domain, the SMRT/SMRTER and Capicua proteins [94]. These interactions, along with interactions between several transcriptional factors, give ataxin-1 its transcriptional repression activity [90,91,93].…”

Section: Wild-type and Mutant Proteinmentioning

confidence: 99%

See 1 more Smart Citation

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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Characterization of the AXH domain of Ataxin‐1 using enhanced sampling and functional mode analysis

Cited by 21 publications

References 35 publications

Protein Environment: A Crucial Triggering Factor in Josephin Domain Aggregation: The Role of 2,2,2-Trifluoroethanol

Protein Environment: A Crucial Triggering Factor in Josephin Domain Aggregation: The Role of 2,2,2-Trifluoroethanol

Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

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