Off-pathway aggregation can inhibit fibrillation at high protein concentrations

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Ribosomal protein S6 fibrillates readily at slightly elevated temperatures and acidic pH. We find that S6 fibrillation is retarded rather than favored when the protein concentration is increased above a threshold concentration of around 3.5mg/mL. We name this threshold concentration C(FR), the concentration at which fibrillation is retarded. Our data are consistent with a model in which this inhibition is due to the formation of an off-pathway oligomeric species with native-like secondary structure. The oligomeric species dominates at high protein concentrations but exists in dynamic equilibrium with the monomer so that seeding with fibrils can overrule oligomer formation and favors fibrillation under C(FR) conditions. Thus, fibrillation competes with formation of off-pathway oligomers, probably due to a monomeric conversion step that is required to commit the protein to the fibrillation pathway. The S6 oligomer is resistant to pepsin digestion. We also report that S6 forms different types of fibrils dependent on protein concentration. Our observations highlight the multitude of conformational states available to proteins under destabilizing conditions.
Original languageEnglish
JournalBBA General Subjects
Volume1834
Issue3
Pages (from-to)677-687
Number of pages11
ISSN0304-4165
DOIs
Publication statusPublished - Mar 2013

    Research areas

  • Amyloid formation;, s6, Soluble oligomers, Proteolysis, Fibril morphology, Acid cleavage

See relations at Aarhus University Citationformats

ID: 52156857