Conformational fluctuations of the AXH monomer of Ataxin-1

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

doi:10.1002/prot.24954

Cited by 31 publications

(48 citation statements)

References 42 publications

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“…Based on those findings, and in accordance with previous observations, it has been suggested that interactions leading to the dimer formation might be able to stabilize the Nter region of the AXH m , which is involved in the dimeric interface . However, several issues concerning the protein‐protein interactions characterizing AXH conformational stability and, more generally, a dynamic description of protein conformational changes at dimer interface, are still unknown.…”

Section: Introductionsupporting

confidence: 80%

“…Recently, classical and biased molecular dynamics (MD) has been applied to investigate the extensive conformational fluctuation of the Nter tail of the AXH monomer (AXH m ) in solution . It has been demonstrated that AXH m is characterized by a relatively stable structure with, in general, highly conserved domains, except for the Nter tail switching between several conformations.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Ataxin-1 is the protein responsible for the Spinocerebellar ataxia type 1, an incurable neurodegenerative disease caused by polyglutamine expansion. The AXH domain plays a pivotal role in physiological functions of Ataxin-1. In Spinocerebellar ataxia 1, the AXH domain is involved in the misfolding and aggregation pathway. Here molecular modeling is applied to investigate the protein-protein interactions contributing to the AXH dimer stability. Particular attention is focused on: (i) the characterization of AXH monomer-monomer interface; (ii) the molecular description of the AXH monomer-monomer interaction dynamics. Technically, an approach based on functional mode analysis, here applied to replica exchange molecular dynamics trajectories, was employed. The findings of this study are consistent with previous experimental results and elucidate the pivotal role of the I580 residue in mediating the AXH monomer-monomer interaction dynamics.

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Section: Introductionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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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“…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%

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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Conformational fluctuations of the AXH monomer of Ataxin-1

Cited by 31 publications

References 42 publications

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

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

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

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

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