Enhanced Molecular Mobility of Ordinarily Structured Regions Drives Polyglutamine Disease

Abstract

Background: Polyglutamine tract expansion within disease-associated proteins leads to protein aggregation and disease. Results: Molecular mobility of a single ␣-helix within ataxin-3 positively scales with polyglutamine tract length and drives misfolding and aggregation. Conclusion: Polyglutamine expansion allosterically enhances the molecular dynamics of folded regions to trigger amyloid-like fibril formation. Significance: This work resolves the mechanistic link between polyglutamine tract length and aggregation.

Ubiquitin Substrates Dramatically Increase Ataxin3 Deubiquitinating Activity: Allosteric crosstalk connects three distinct sites

“…Ubiquitin binding at Site 2 might affect catalysis by perturbing the conformation of the Josephin domain; however, it is less straightforward to rationalize how ubiquitin binding to the tandem UIMs could have a similar effect, given the UIMs' distance from the catalytic center. However, we note that expansion of the ataxin3 polyglutamine tract-which is adjacent to the UIMs-promotes local unfolding within the Josephin domain (54,55), proving that information about the protein's C-terminal region is somehow communicated with the catalytic domain.…”

Thermodynamic and kinetic stability of the Josephin Domain closed arrangement: evidences from replica exchange molecular dynamics

“…Prompted by evidences indicating an intimate interconnection between the JD plasticity and AT-3 aggregation propensity [27], this work focused on the application of computational molecular modeling to investigate JD conformational transition from a kinetic and thermodynamic point of view. In a greater detail, the JD conformational accessible states were thoroughly sampled by REMD simulations.…”

“…On the other hand, ambient conditions that have already shown to affect JD aggregation dynamics and kinetics (i.e., variation in pH or temperature, point mutations [26, 47], interaction with binders [21, 29, 68], interaction with surfaces [48]) might be simulated to verify their potential effect on JD structure. Given the already known intimate relationship between the JD structural plasticity and aggregation propensity [27], the identification of specific JD amyloidogenic conformations might open new routes for the design of novel rational drugs able to drive the JD thermodynamic and kinetic stability toward specific non-amyloidogenic conformations.…”

“…In this regard, experimental studies have demonstrated that the first step of AT3 fibrillogenesis is JD-mediated [22, 25–27]. …”

“…Moreover, we suggested that the peptides sequence Lue84-Trp87 may be relevant for aberrant aggregation in a second step of the JD-JD binding, whereas the first step is mainly mediated by other residues such as Arg101. In this connection a recent experimental work [27] highlighted a transient local unfolding of α4, and consequent exposure of backbone amides to the solvent, able to trigger the AT-3 aggregation.…”