umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Mechanisms of Protein Oligomerization: Inhibitor of Functional Amyloids Templates α-Synuclein Fibrillation
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Show others and affiliations
2012 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, no 7, 3439-3444 p.Article in journal (Refereed) Published
Abstract [en]

Small organic molecules that inhibit functional bacterial amyloid fibers, curli, are promising new antibiotics. Here we investigated the mechanism by which the ring-fused 2-pyridone FN075 inhibits fibrillation of the curli protein CsgA. Using a variety of biophysical techniques, we found that FN075 promotes CsgA to form off-pathway, non-amyloidogenic oligomeric species. In light of the generic properties of amyloids, we tested whether FN075 would also affect the fibrillation reaction of human α-synuclein, an amyloid-forming protein involved in Parkinson's disease. Surprisingly, FN075 stimulates α-synuclein amyloid fiber formation as measured by thioflavin T emission, electron microscopy (EM), and atomic force microscopy (AFM). NMR data on (15)N-labeled α-synuclein show that upon FN075 addition, α-synuclein oligomers with 7 nm radius form in which the C-terminal 40 residues remain disordered and solvent exposed. The polypeptides in these oligomers contain β-like secondary structure, and the oligomers are detectable by AFM, EM, and size-exclusion chromatography (SEC). Taken together, FN075 triggers oligomer formation of both proteins: in the case of CsgA, the oligomers do not proceed to fibers, whereas for α-synuclein, the oligomers are poised to rapidly form fibers. We conclude that there is a fine balance between small-molecule inhibition and templation that depends on protein chemistry.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2012. Vol. 134, no 7, 3439-3444 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-52526DOI: 10.1021/ja209829mPubMedID: 22260746OAI: oai:DiVA.org:umu-52526DiVA: diva2:505522
Available from: 2012-02-24 Created: 2012-02-24 Last updated: 2017-12-07Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Horvath, IstvanWeise, Christoph FAndersson, Emma KChorell, ErikSellstedt, MagnusBengtsson, ChristofferOlofsson, AndersChapman, MatthewWolf-Watz, MagnusAlmqvist, FredrikWittung-Stafshede, Pernilla

Search in DiVA

By author/editor
Horvath, IstvanWeise, Christoph FAndersson, Emma KChorell, ErikSellstedt, MagnusBengtsson, ChristofferOlofsson, AndersChapman, MatthewWolf-Watz, MagnusAlmqvist, FredrikWittung-Stafshede, Pernilla
By organisation
Department of ChemistryDepartment of Medical Biochemistry and BiophysicsUmeå Centre for Microbial Research (UCMR)
In the same journal
Journal of the American Chemical Society
Chemical Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 417 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf