Self-Assembly and Conformational Heterogeneity of the AXH Domain of Ataxin-1: An Unusual Example of a Chameleon Fold

Chiara, Cesira de; Rees, Martin; Menon, Raj P.; Pauwels, Kris; Lawrence, Ceri; Konarev, Petr V.; Svergun, Dmitri I.; Martin, Stephen R.; Chen, Yu Wai; Pastore, Annalisa

doi:10.1016/j.bpj.2013.01.048

Cited by 21 publications

(84 citation statements)

References 33 publications

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“…Using a combination of NMR, analytical ultracentrifugation, X-ray and small angle scattering, we have previously shown that the observed behaviour is consistent with the presence of a monomer-dimer-tetramer equilibrium over a wide range of concentrations as well as with conformational heterogeneity of the different protomers [20]. When we titrated the 15 N-labelled AXH with unlabelled L-CICp, the NMR spectrum underwent a dramatic change ( Figure 2A , bottom ).…”

Section: Resultssupporting

confidence: 64%

“…It is clear from these plots that the AXH structure is overall rigid with the exception of the AXH N-terminal tail and sparse residues located in short loop regions. Horizontal straight lines indicate the equivalent average values observed in isolated AXH [20]. C) Size exclusion chromatography study.…”

Section: Resultsmentioning

confidence: 99%

“…We have recently demonstrated that the AXH domain has an unusual chameleon oligonucleotide-binding (OB) fold, a structural motif involved in nucleic acid and protein recognition [19]. In solution, the isolated AXH forms a complex equilibrium between monomer, dimer, tetramer and higher molecular weight species that are on-pathway to protein misfolding and fiber formation [20]. The presence of the AXH domain favours formation of intra-nuclear aggregates of expanded ATX1 in eukaryotic cells [5].…”

Section: Introductionmentioning

confidence: 99%

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Protein-Protein Interactions as a Strategy towards Protein-Specific Drug Design: The Example of Ataxin-1

et al. 2013

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A main challenge for structural biologists is to understand the mechanisms that discriminate between molecular interactions and determine function. Here, we show how partner recognition of the AXH domain of the transcriptional co-regulator ataxin-1 is fine-tuned by a subtle balance between self- and hetero-associations. Ataxin-1 is the protein responsible for the hereditary spinocerebellar ataxia type 1, a disease linked to protein aggregation and transcriptional dysregulation. Expansion of a polyglutamine tract is essential for ataxin-1 aggregation, but the sequence-wise distant AXH domain plays an important aggravating role in the process. The AXH domain is also a key element for non-aberrant function as it intervenes in interactions with multiple protein partners. Previous data have shown that AXH is dimeric in solution and forms a dimer of dimers when crystallized. By solving the structure of a complex of AXH with a peptide from the interacting transcriptional repressor CIC, we show that the dimer interface of AXH is displaced by the new interaction and that, when blocked by the CIC peptide AXH aggregation and misfolding are impaired. This is a unique example in which palindromic self- and hetero-interactions within a sequence with chameleon properties discriminate the partner. We propose a drug design strategy for the treatment of SCA1 that is based on the information gained from the AXH/CIC complex.

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Section: Resultssupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein-Protein Interactions as a Strategy towards Protein-Specific Drug Design: The Example of Ataxin-1

et al. 2013

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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].…”

Section: Wild-type and Mutant Proteinmentioning

confidence: 99%

“…The increased polyQ stretch not only increases the tendency to aggregate, but also leads to conformational changes of other regions and domains of the SCA proteins. In the case of SCA1, conformational changes to the AXH domain, along with its ability to fold leads to the potential contribution of misfolded protein aggregation [92,98,99].…”

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

et al. 2015

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In this paper, we report the results of molecular dynamics simulations of AXH monomer of Ataxin-1. The AXH domain plays a crucial role in Ataxin-1 aggregation, which accompanies the initiation and progression of Spinocerebellar ataxia type 1. Our simulations involving both classical and replica exchange molecular dynamics, followed by principal component analysis of the trajectories obtained, reveal substantial conformational fluctuations of the protein structure, especially in the N-terminal region. We show that these fluctuations can be generated by thermal noise since the free energy barriers between conformations are small enough for thermally stimulated transitions. In agreement with the previous experimental findings, our results can be considered as a basis for a future design of ataxin aggregation inhibitors that will require several key conformations identified in the present study as molecular targets for ligand binding.

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Self-Assembly and Conformational Heterogeneity of the AXH Domain of Ataxin-1: An Unusual Example of a Chameleon Fold

Cited by 21 publications

References 33 publications

Protein-Protein Interactions as a Strategy towards Protein-Specific Drug Design: The Example of Ataxin-1

Protein-Protein Interactions as a Strategy towards Protein-Specific Drug Design: The Example of Ataxin-1

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

Conformational fluctuations of the AXH monomer of Ataxin-1

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