Experimental diagnostic of sequence-variant dynamic perturbations revealed by broadband dielectric spectroscopy.

Autor: Bourgeat L; Univ Lyon, CNRS, INSA Lyon, Université Claude Bernard Lyon 1, Ecole Centrale de Lyon, Ampère, UMR5005, 69622 Villeurbanne, France; Univ Lyon, CNRS, IMP, 69622, Villeurbanne, France., Pacini L; Univ Lyon, CNRS, INSA Lyon, Université Claude Bernard Lyon 1, Ecole Centrale de Lyon, Ampère, UMR5005, 69622 Villeurbanne, France; Institut Rhônalpin des systèmes complexes, IXXI-ENS-Lyon, 69007, Lyon, France., Serghei A; Univ Lyon, CNRS, IMP, 69622, Villeurbanne, France., Lesieur C; Univ Lyon, CNRS, INSA Lyon, Université Claude Bernard Lyon 1, Ecole Centrale de Lyon, Ampère, UMR5005, 69622 Villeurbanne, France; Institut Rhônalpin des systèmes complexes, IXXI-ENS-Lyon, 69007, Lyon, France. Electronic address: claire.lesieur@ens-lyon.fr.
Jazyk: angličtina
Zdroj: Structure (London, England : 1993) [Structure] 2021 Dec 02; Vol. 29 (12), pp. 1419-1429.e3. Date of Electronic Publication: 2021 May 28.
DOI: 10.1016/j.str.2021.05.005
Abstrakt: Genetic diversity leads to protein robustness, adaptability, and failure. Some sequence variants are structurally robust but functionally disturbed because mutations bring the protein onto unfolding/refolding routes resulting in misfolding diseases (e.g., Parkinson). We assume dynamic perturbations introduced by mutations foster the alternative unfolding routes and test this possibility by comparing the unfolding dynamics of the heat-labile enterotoxin B pentamers and the cholera toxin B pentamers, two pentamers structurally and functionally related and robust to 17 sequence variations. The B-subunit thermal unfolding dynamics are monitored by broadband dielectric spectroscopy in nanoconfined and weakly hydrated conditions. Distinct dielectric signals reveal the different B-subunits unfolding dynamics. Combined with network analyses, the experiments pinpoint the role of three mutations A1T, E7D, and E102A, in diverting LTB 5 to alternative unfolding routes that protect LTB 5 from dissociation. Altogether, the methodology diagnoses dynamics faults that may underlie functional disorder, drug resistance, or higher virulence of sequence variants.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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