bi036248t_si_001.pdf (157.79 kB)
Folding into a β-Hairpin Can Prevent Amyloid Fibril Formation†
journal contribution
posted on 2004-04-27, 00:00 authored by Waltteri Hosia, Niklas Bark, Edvards Liepinsh, Agneta Tjernberg, Bengt Persson, Dan Hallén, Johan Thyberg, Jan Johansson, Lars TjernbergThe tetrapeptide KFFE is one of the shortest amyloid fibril-forming peptides described. Herein,
we have investigated how the structural environment of this motif affects polymerization. Using a turn
motif (YNGK) or a less rigid sequence (AAAK) to fuse two KFFE tetrapeptides, we show by several
biophysical methods that the amyloidogenic properties are strongly dependent on the structural environment.
The dodecapeptide KFFEAAAKKFFE forms abundant thick fibril bundles. Freshly dissolved
KFFEAAAKKFFE is monomeric and shows mainly disordered secondary structure, as evidenced by circular
dichroism, NMR spectroscopy, hydrogen/deuterium exchange measurements, and molecular modeling
studies. In sharp contrast, the dodecapeptide KFFEYNGKKFFE does not form fibrils but folds into a
stable β-hairpin. This structure can oligomerize into a stable 12-mer and multiples thereof, as shown by
size exclusion chromatography, sedimentation analysis, and electrospray mass spectrometry. These data
indicate that the structural context in which a potential fibril forming sequence is present can prevent
fibril formation by favoring self-limiting oligomerization over polymerization.