Aggregation Pathways of Native‐Like Ubiquitin Promoted by Single‐Point Mutation, Metal Ion Concentration, and Dielectric Constant of the Medium

Aggregation Pathways of Native‐Like Ubiquitin Promoted by Single‐Point Mutation, Metal Ion... Ubiquitin‐positive protein aggregates are biomarkers of neurodegeneration, but the molecular mechanism responsible for their formation and accumulation is still unclear. Possible aggregation pathways of human ubiquitin (hUb) promoted by both intrinsic and extrinsic factors, are here investigated. By a computational analysis, two different hUb dimers are indicated as possible precursors of amyloid‐like structures, but their formation is disfavored by an electrostatic repulsion involving Glu16 and other carboxylate residues present at the dimer interface. Experimental data on the E16V mutant of hUb shows that this single‐point mutation, although not affecting the overall protein conformation, promotes protein aggregation. It is sufficient to shift the same mutation by only two residues (E18V) to regain the behavior of wild‐type hUb. The neutralization of Glu16 negative charge by a metal ion and a decrease of the dielectric constant of the medium by addition of trifluoroethanol (TFE), also promote hUb aggregation. The outcomes of this research have important implications for the prediction of physiological parameters that favor aggregate formation. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Chemistry - A European Journal Wiley

Aggregation Pathways of Native‐Like Ubiquitin Promoted by Single‐Point Mutation, Metal Ion Concentration, and Dielectric Constant of the Medium

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Publisher
Wiley
Copyright
© 2018 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim
ISSN
0947-6539
eISSN
1521-3765
D.O.I.
10.1002/chem.201705543
Publisher site
See Article on Publisher Site

Abstract

Ubiquitin‐positive protein aggregates are biomarkers of neurodegeneration, but the molecular mechanism responsible for their formation and accumulation is still unclear. Possible aggregation pathways of human ubiquitin (hUb) promoted by both intrinsic and extrinsic factors, are here investigated. By a computational analysis, two different hUb dimers are indicated as possible precursors of amyloid‐like structures, but their formation is disfavored by an electrostatic repulsion involving Glu16 and other carboxylate residues present at the dimer interface. Experimental data on the E16V mutant of hUb shows that this single‐point mutation, although not affecting the overall protein conformation, promotes protein aggregation. It is sufficient to shift the same mutation by only two residues (E18V) to regain the behavior of wild‐type hUb. The neutralization of Glu16 negative charge by a metal ion and a decrease of the dielectric constant of the medium by addition of trifluoroethanol (TFE), also promote hUb aggregation. The outcomes of this research have important implications for the prediction of physiological parameters that favor aggregate formation.

Journal

Chemistry - A European JournalWiley

Published: Jan 15, 2018

Keywords: ; ; ; ; ;

References

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