The 2.2‐Angstrom resolution crystal structure of the carboxy‐terminal region of ataxin‐3

Zhemkov, Vladimir; Kulminskaya, Anna A.; Bezprozvanny, Ilya; Kim, Meewhi

doi:10.1002/2211-5463.12029

Cited by 15 publications

(7 citation statements)

References 60 publications

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“…MBP provides a stable solubilisation domain and has been used previously in the investigation of truncated ataxin-3 constructs. 36 Remarkably, native ESI-MS of this protein (MBP-183-221) in the presence of QBP1 resulted in a 1:1 complex (Figure 8(a) and Supplementary Table 2). Treatment with TEV protease to remove the ataxin-3derived residues abrogated the QBP1 interaction, indicative of a specific interaction between residues 183-221 of ataxin-3 and QBP1 (Figure 8(b)).…”

Section: Residues 182-221 Of Ataxin-3 Bind Qbp1mentioning

confidence: 94%

Identification of a novel site of interaction between ataxin-3 and the amyloid aggregation inhibitor polyglutamine binding peptide 1

Knight

Karamanos

Radford

et al. 2017

Eur J Mass Spectrom (Chichester)

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Amyloid diseases represent a growing social and economic burden in the developed world. Understanding the assembly pathway and the inhibition of amyloid formation is key to developing therapies to treat these diseases. The neurodegenerative condition Machado–Joseph disease is characterised by the self-aggregation of the protein ataxin-3. Ataxin-3 consists of a globular N-terminal Josephin domain, which can aggregate into curvilinear protofibrils, and an unstructured, dynamically disordered C-terminal domain containing three ubiquitin interacting motifs separated by a polyglutamine stretch. Upon expansion of the polyglutamine region above 50 residues, ataxin-3 undergoes a second stage of aggregation in which long, straight amyloid fibrils form. A peptide inhibitor of polyglutamine aggregation, known as polyQ binding peptide 1, has been shown previously to prevent the maturation of ataxin-3 fibrils. However, the mechanism of this inhibition remains unclear. Using nanoelectrospray ionisation-mass spectrometry, we demonstrate that polyQ binding peptide 1 binds to monomeric ataxin-3. By investigating the ability of polyQ binding peptide 1 to bind to truncated ataxin-3 constructs lacking one or more domains, we localise the site of this interaction to a 39-residue sequence immediately C-terminal to the Josephin domain. The results suggest a new mechanism for the inhibition of polyglutamine aggregation by polyQ binding peptide 1 in which binding to a region outside of the polyglutamine tract can prevent fibril formation, highlighting the importance of polyglutamine flanking regions in controlling aggregation and disease.

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Section: Residues 182-221 Of Ataxin-3 Bind Qbp1mentioning

confidence: 94%

Identification of a novel site of interaction between ataxin-3 and the amyloid aggregation inhibitor polyglutamine binding peptide 1

Knight

Karamanos

Radford

et al. 2017

Eur J Mass Spectrom (Chichester)

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“…PolyQ regions are generally preceded by helical conformation and followed by a random coil ( Totzeck et al 2017 ). A recent NMR structural study of various polyQ variants with their sequence context in Huntingtin demonstrated that the polyQ prolongs the preceding helical conformation ( Urbanek et al 2020 ); it was shown previously that the helical structure of polyQ is stabilized by intrahelical hydrogen bonds mediated by the side chains of the glutamine residues ( Zhemkov et al 2016 ; Escobedo et al, 2019 ). In Huntingtin and other proteins, polyQ is followed C-terminally by a polyP or Pro-rich region.…”

Section: Sequence and Context Structure Impositionmentioning

confidence: 99%

Between Interactions and Aggregates: The PolyQ Balance

Mier

Andrade‐Navarro

2021

Genome Biology and Evolution

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Polyglutamine regions (polyQ) are highly abundant consecutive runs of glutamine residues. They have been generally studied in relation to the so-called polyQ-associated diseases, characterized by protein aggregation caused by the expansion of the polyglutamine tract via a CAG-slippage mechanism. However, more than 4800 human proteins contain a polyQ, and only 9 of these regions are known to be associated with disease. Computational sequence studies and experimental structure determinations are completing a more interesting picture in which polyQ emerge as a motif for modulation of protein-protein interactions. But long polyQ regions may lead to an excess of interactions, and produce aggregates. Within this mechanistic perspective of polyQ function and malfunction, we discuss polyQ definition and properties such as variable codon usage, sequence and context structure imposition, functional relevance, evolutionary patterns in species-centered analyses, and open resources.

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“…Conformational variability of the polyQ domain was also recently observed in crystal structures of the carboxy‐terminal region of ataxin‐3. 115 There are potential caveats, however, in that these structural elements may be induced via the crystallization process or the inclusion of fusion partners to htt that can also induce secondary structure. An α-helical structure has been observed in monomeric polyQ tracts within the androgen receptor by NMR, 116 and CD spectroscopy suggests that this α-helical content increases with polyQ length.…”

Section: Structural Features Of Monomeric Polyq Peptides and Polyq-comentioning

confidence: 99%

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

et al. 2017

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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.

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The 2.2‐Angstrom resolution crystal structure of the carboxy‐terminal region of ataxin‐3

Cited by 15 publications

References 60 publications

Identification of a novel site of interaction between ataxin-3 and the amyloid aggregation inhibitor polyglutamine binding peptide 1

Identification of a novel site of interaction between ataxin-3 and the amyloid aggregation inhibitor polyglutamine binding peptide 1

Between Interactions and Aggregates: The PolyQ Balance

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

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