Capturing the Conformational Ensemble of the Mixed Folded Polyglutamine Protein Ataxin-3

Sicorello, Alessandro; Różycki, Bartosz; Konarev, Petr V.; Svergun, Dmitri I.; Pastore, Annalisa

doi:10.1016/j.str.2020.09.010

Cited by 14 publications

(11 citation statements)

References 104 publications

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“…Both techniques have been used extensively to generate ensemble representations of IDPs or multidomain proteins which contain a significant portion of IDRs ( Bernadó et al, 2005b ; Merchant et al, 2007 ; Holmstrom et al, 2018 ). In terms of aggregating proteins, integrative studies have been performed in order to describe ensembles of ataxin ( Sicorello et al, 2021 ), α-syn ( Schwalbe et al, 2014 ; Chen et al, 2021 ), amyloid β ( Sgourakis et al, 2007 ) and tau ( Chen et al, 2019 ; Stelzl et al, 2022 ) among others ( Strodel, 2021 ).…”

Section: Experimental Methods Used To Guide the Generation Of Protein...mentioning

confidence: 99%

“…For protein precursors that are initially folded (e.g., β 2 m, light chains, transthyretin; Iadanza et al, 2018 ), local protein motions which lead to exposure of hydrophobic/aggregation-prone regions (APRs) ( Beerten et al, 2012 ; Houben et al, 2022 ) that are normally buried in the native structure, have been suggested as the drivers of self-assembly. For misfolding-prone proteins that contain long disordered regions (IDRs) dispersed within, or at the termini, of folded domains (e.g., prions and polyQ-containing proteins), the initiating stages of aggregation may be dominated by the IDR, by interactions involving the folded domain, or both ( Scarff et al, 2013 ; Singh and Udgaonkar, 2015 ; Sicorello et al, 2018 , 2021 ; Lieberman et al, 2019 ). And, while it is now straightforward to predict the presence of APRs in protein sequences ( Tsolis et al, 2013 ), these regions cannot be solely responsible for driving the initial stages of aggregation, since it is well-known that regions that flank these sequences can play a pivotal role in controlling assembly ( Ulamec et al, 2020 ).…”

Section: Misfolding Proteins Across the Flexibility Scalementioning

confidence: 99%

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Generating Ensembles of Dynamic Misfolding Proteins

2022

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The early stages of protein misfolding and aggregation involve disordered and partially folded protein conformers that contain a high degree of dynamic disorder. These dynamic species may undergo large-scale intra-molecular motions of intrinsically disordered protein (IDP) precursors, or flexible, low affinity inter-molecular binding in oligomeric assemblies. In both cases, generating atomic level visualization of the interconverting species that captures the conformations explored and their physico-chemical properties remains hugely challenging. How specific sub-ensembles of conformers that are on-pathway to aggregation into amyloid can be identified from their aggregation-resilient counterparts within these large heterogenous pools of rapidly moving molecules represents an additional level of complexity. Here, we describe current experimental and computational approaches designed to capture the dynamic nature of the early stages of protein misfolding and aggregation, and discuss potential challenges in describing these species because of the ensemble averaging of experimental restraints that arise from motions on the millisecond timescale. We give a perspective of how machine learning methods can be used to extract aggregation-relevant sub-ensembles and provide two examples of such an approach in which specific interactions of defined species within the dynamic ensembles of α-synuclein (αSyn) and β2-microgloblulin (β2m) can be captured and investigated.

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Section: Experimental Methods Used To Guide the Generation Of Protein...mentioning

confidence: 99%

Section: Misfolding Proteins Across the Flexibility Scalementioning

confidence: 99%

Generating Ensembles of Dynamic Misfolding Proteins

2022

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“…[22] We recently demonstrated that, although generally more flexible, the C-terminus of ataxin-3 contains well-defined secondary structure elements. [23] Ataxin-3 is linked to the progressive neurodegenerative Machado-Joseph disease (MJD; MIM catalogue no. 109150), also known as spinocerebellar ataxia type 3 (or SCA3).…”

Section: A Striking Example Of a Partner-orphan Mechanism: The Role Of Ubiquitin Binding In Ataxin-3 Aggregationmentioning

confidence: 99%

“…[ 22 ] We recently demonstrated that, although generally more flexible, the C‐terminus of ataxin‐3 contains well‐defined secondary structure elements. [ 23 ]…”

Section: A Striking Example Of a Partner‐orphan Mechanism: The Role Of Ubiquitin Binding In Ataxin‐3 Aggregationmentioning

confidence: 99%

The seesaw between normal function and protein aggregation: How functional interactions may increase protein solubility

2021

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Protein aggregation has been studied for at least 3 decades, and many of the principles that regulate this event are relatively well understood. Here, however, we present a different perspective to explain why proteins aggregate: we argue that aggregation may occur as a side-effect of the lack of one or more natural partners that, under physiologic conditions, would act as chaperones. This would explain why the same surfaces that have evolved for functional purposes are also those that favour aggregation. In the course of reviewing this field, we substantiate our hypothesis with three paradigmatic examples that argue for the generality of our proposal. An obvious corollary of this hypothesis is, of course, that targeting the physiological partners of a protein could be the most direct and specific approach to designing anti-aggregation molecules. Our analysis may thus inform a different strategy for combating diseases of protein aggregation and misfolding.

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“…AT-3 is a multi-domain polyglutamine deubiquitinating enzyme used as a model system to study polyglutamine neurodegenerative diseases ( Burnett et al, 2003 ; Carvalho et al, 2018 ; Invernizzi et al, 2012 ). AT-3 contains two UIM regions (UIM1 and UIM2) in the central part of the protein, surrounded by disordered regions ( Burnett et al, 2003 ; Invernizzi et al, 2013 ; Masino et al, 2003 ; Sicorello et al, 2018 , 2021 ). AT-3 also undergoes alternative splicing, and its isoforms differ in the C-terminus ( Harris et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin Interacting Motifs: Duality Between Structured and Disordered Motifs

Lambrughi

Maiani

Fas

et al. 2021

Front. Mol. Biosci.

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Ubiquitin is a small protein at the heart of many cellular processes, and several different protein domains are known to recognize and bind ubiquitin. A common motif for interaction with ubiquitin is the Ubiquitin Interacting Motif (UIM), characterized by a conserved sequence signature and often found in multi-domain proteins. Multi-domain proteins with intrinsically disordered regions mediate interactions with multiple partners, orchestrating diverse pathways. Short linear motifs for binding are often embedded in these disordered regions and play crucial roles in modulating protein function. In this work, we investigated the structural propensities of UIMs using molecular dynamics simulations and NMR chemical shifts. Despite the structural portrait depicted by X-crystallography of stable helical structures, we show that UIMs feature both helical and intrinsically disordered conformations. Our results shed light on a new class of disordered UIMs. This group is here exemplified by the C-terminal domain of one isoform of ataxin-3 and a group of ubiquitin-specific proteases. Intriguingly, UIMs not only bind ubiquitin. They can be a recruitment point for other interactors, such as parkin and the heat shock protein Hsc70-4. Disordered UIMs can provide versatility and new functions to the client proteins, opening new directions for research on their interactome.

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Capturing the Conformational Ensemble of the Mixed Folded Polyglutamine Protein Ataxin-3

Cited by 14 publications

References 104 publications

Generating Ensembles of Dynamic Misfolding Proteins

Generating Ensembles of Dynamic Misfolding Proteins

The seesaw between normal function and protein aggregation: How functional interactions may increase protein solubility

Ubiquitin Interacting Motifs: Duality Between Structured and Disordered Motifs

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