Between Interactions and Aggregates: The PolyQ Balance

Abstract

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.

The Josephin domain (JD) containing proteins are predicted to bind to the same interactors: Implications for spinocerebellar ataxia type 3 (SCA3) studies using Drosophila melanogaster mutants

“…The expanded polyQ tract leads to structural changes of the translated protein, that alters native PPIs, and thus, the normal protein activity ( Lim et al, 2006 ; Hosp et al, 2015 ; Rocha et al, 2019 ). It should be noted that the polyQ is located between a disordered region and a coiled-coil region used for PPI ( Schaefer et al, 2012 ; Mier and Andrade-Navarro, 2021 ). It has been hypothesized that when expanded, the polyQ region would adopt a helical conformation, extending the preceding helix, and thus making the PPI interactions stronger ( Schaefer et al, 2012 ; Petrakis et al, 2013 ; Mier and Andrade-Navarro, 2021 ).…”

“…It should be noted that the polyQ is located between a disordered region and a coiled-coil region used for PPI ( Schaefer et al, 2012 ; Mier and Andrade-Navarro, 2021 ). It has been hypothesized that when expanded, the polyQ region would adopt a helical conformation, extending the preceding helix, and thus making the PPI interactions stronger ( Schaefer et al, 2012 ; Petrakis et al, 2013 ; Mier and Andrade-Navarro, 2021 ). For instance, VCP delays exp ataxin-3 for proteasome degradation, because exp ataxin-3 is not dissociated from E4B protein (that endorses ataxin-3 for degradation; Matsumoto et al, 2004 ).…”

“…Furthermore, since interactors that show six or more interactions at the polyQ tract have been associated with low confidence predictions ( Rocha et al, 2019 ), in order to be conservative, these were excluded from the analyses ( Supplementary Table S8 ). It should be noted that, the mechanisms by which polyQ modulate PPI might be through the expansion of sequence-adjacent coiled-coil regions that facilitates the interaction with a coiled-coil region from another protein ( Mier and Andrade-Navarro, 2021 ). For wt and exp ataxin-3 and JosL, interaction regions were identified by looking for amino acid positions that interact with more than 50% of the interactors and that are less than three consecutive amino acids apart from each other.…”

“…Although polyglutamine repeats (polyQ) are the most abundant homorepeats in eukaryotic proteomes ( Mier and Andrade-Navarro, 2021 ), they are frequently associated with debilitating and incurable neurodegenerative disorders, known as polyQ diseases ( Heemels, 2016 ; Gitler et al, 2017 ). PolyQ diseases, are a family of nine rare dominantly transmitted disorders caused by a pathogenic expansion of CAG (Cytosine-Adenosine-Guanine) trinucleotide repeats in the corresponding coding region of the nine genes (Androgen receptor, Atrophin 1, Ataxin- 1, 2, 3, 7, calcium voltage-gated channel subunit alpha 1A, Huntingtin, and TATA-binding protein).…”

The stress granule protein G3BP1 reduces the levels of polyglutamine proteins and alleviates spinocerebellar ataxia associated deficits

“…5 j-o). Aggregation is a crucial step in disease pathogenesis; although large macromolecular inclusions containing polyQ proteins are currently regarded as not being the primary drivers of cell toxicity, the tendency of polyQ-containing proteins to self-assemble and engage in abnormal interactions is regarded as a common mechanism responsible for the intrinsic toxicity of these proteins 56,57 . Our results indicate that G3BP1 is able to counter mutant protein aggregation to an extent, suggesting that G3BP1 has a protective role against the toxicity of these disease-associated proteins.…”