Mechanisms of protein oligomerization: inhibitor of functional amyloids templates α-synuclein fibrillation

J Am Chem Soc. 2012 Feb 22;134(7):3439-44. doi: 10.1021/ja209829m. Epub 2012 Feb 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / antagonists & inhibitors*
  • Amyloid / metabolism
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Escherichia coli / drug effects
  • Escherichia coli / metabolism
  • Escherichia coli Proteins / metabolism*
  • Humans
  • Parkinson Disease / metabolism
  • Pyridones / chemistry*
  • Pyridones / pharmacology*
  • alpha-Synuclein / metabolism*


  • Amyloid
  • Anti-Bacterial Agents
  • Escherichia coli Proteins
  • Pyridones
  • alpha-Synuclein
  • csgA protein, E coli
  • 2-hydroxypyridine