Dataset Information

Between Interactions and Aggregates: The PolyQ Balance.

ABSTRACT: Polyglutamine (polyQ) regions 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 polyQ tract via a CAG-slippage mechanism. However, more than 4,800 human proteins contain a polyQ, and only nine 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.

SUBMITTER: Mier P

PROVIDER: S-EPMC8763233 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Between Interactions and Aggregates: The PolyQ Balance.

Mier Pablo P Andrade-Navarro Miguel A MA

Genome biology and evolution 20211101 11

Polyglutamine (polyQ) regions 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 polyQ tract via a CAG-slippage mechanism. However, more than 4,800 human proteins contain a polyQ, and only nine of these regions are known to be associated with disease. Computational sequence studies and experimental structure determinations are compl ...[more]

PMID: 34791220

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Project description:Nine neurodegenerative disorders, called polyglutamine (polyQ) diseases, are characterized by the formation of intranuclear amyloid-like aggregates by nine proteins containing a polyQ tract above a threshold length. These insoluble aggregates and/or some of their soluble precursors are thought to play a role in the pathogenesis. The mechanism by which polyQ expansions trigger the aggregation of the relevant proteins remains, however, unclear. In this work, polyQ tracts of different lengths were inserted into a solvent-exposed loop of the β-lactamase BlaP and the effects of these insertions on the properties of BlaP were investigated by a range of biophysical techniques. The insertion of up to 79 glutamines does not modify the structure of BlaP; it does, however, significantly destabilize the enzyme. The extent of destabilization is largely independent of the polyQ length, allowing us to study independently the effects intrinsic to the polyQ length and those related to the structural integrity of BlaP on the aggregating properties of the chimeras. Only chimeras with 55Q and 79Q readily form amyloid-like fibrils; therefore, similarly to the proteins associated with diseases, there is a threshold number of glutamines above which the chimeras aggregate into amyloid-like fibrils. Most importantly, the chimera containing 79Q forms amyloid-like fibrils at the same rate whether BlaP is folded or not, whereas the 55Q chimera aggregates into amyloid-like fibrils only if BlaP is unfolded. The threshold value for amyloid-like fibril formation depends, therefore, on the structural integrity of the β-lactamase moiety and thus on the steric and/or conformational constraints applied to the polyQ tract. These constraints have, however, no significant effect on the propensity of the 79Q tract to trigger fibril formation. These results suggest that the influence of the protein context on the aggregating properties of polyQ disease-associated proteins could be negligible when the latter contain particularly long polyQ tracts.

Dataset Information

Between Interactions and Aggregates: The PolyQ Balance.

Publications

Between Interactions and Aggregates: The PolyQ Balance.

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