Folding into a beta-hairpin can prevent amyloid fibril formation.
The 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 beta-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.
Hosia
Waltteri
W
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Bark
Niklas
N
Liepinsh
Edvards
E
Tjernberg
Agneta
A
Persson
Bengt
B
Hallén
Dan
D
Thyberg
Johan
J
Johansson
Jan
J
Tjernberg
Lars
L
D020816:Amino Acid Motifs; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D002942:Circular Dichroism; D041961:Deuterium Exchange Measurement; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary
D000682:Amyloid; D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D011108:Polymers