Slow Escape from a Helical Misfolded State of the Pore-Forming Toxin Cytolysin A.
Journal
JACS Au
ISSN: 2691-3704
Titre abrégé: JACS Au
Pays: United States
ID NLM: 101775714
Informations de publication
Date de publication:
23 Aug 2021
23 Aug 2021
Historique:
received:
20
04
2021
entrez:
1
9
2021
pubmed:
2
9
2021
medline:
2
9
2021
Statut:
epublish
Résumé
The pore-forming toxin cytolysin A (ClyA) is expressed as a large α-helical monomer that, upon interaction with membranes, undergoes a major conformational rearrangement into the protomer conformation, which then assembles into a cytolytic pore. Here, we investigate the folding kinetics of the ClyA monomer with single-molecule Förster resonance energy transfer spectroscopy in combination with microfluidic mixing, stopped-flow circular dichroism experiments, and molecular simulations. The complex folding process occurs over a broad range of time scales, from hundreds of nanoseconds to minutes. The very slow formation of the native state occurs from a rapidly formed and highly collapsed intermediate with large helical content and nonnative topology. Molecular dynamics simulations suggest pronounced non-native interactions as the origin of the slow escape from this deep trap in the free-energy surface, and a variational enhanced path-sampling approach enables a glimpse of the folding process that is supported by the experimental data.
Identifiants
pubmed: 34467360
doi: 10.1021/jacsau.1c00175
pmc: PMC8397351
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1217-1230Informations de copyright
© 2021 The Authors. Published by American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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