Amyloid fibrils formed by selective N-, C-terminal sequences of mouse apolipoprotein A-II.
In mice, amyloidogenic type C apolipoprotein A-II (apoA-II) forms amyloid fibrils in age-associated amyloidosis. To understand the mechanism of amyloid fibril formation by apoA-II, we examined the polymerization of synthetic partial peptides of apoA-II in vitro. None of the partial apoA-II peptides polymerized into amyloid fibrils when tested as a single species mixture. We found a unique mechanism in which N- and C-terminal peptides associated into amyloid fibrils in a 1:1 ratio at pH 2.5. The 11-residue amino acid sequence (6-16), which is a common sequence of type B apoA-II and type C apoA-II proteins in amyloidosis-resistant mice and amyloidosis-susceptible mice, respectively, was critical for polymerization into amyloid fibrils. The 18-residue-long amino acid sequence (48-65) is also necessary for nucleation, but not for the extension phase. These findings suggest that there may be different mechanisms underlying the nucleation and extension phases of apoA-II amyloid fibril formation. We also found that amino acid substitutions between type B apoA-II (Pro5, Val38) and type C apoA-II (Gln5, Ala38) did not affect either phase. The strategy of using synthetic partial peptides of amyloidogenic proteins in vitro is a useful system for understanding amyloid fibril formation and for the development of novel therapies.
Sawashita
Jinko
J
Department of Aging Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. jinkos@shinshu-u.ac.jp
Kametani
Fuyuki
F
Hasegawa
Kazuhiro
K
Tsutsumi-Yasuhara
Shinobu
S
Zhang
Beiru
B
Yan
Jingmin
J
Mori
Masayuki
M
Naiki
Hironobu
H
Higuchi
Keiichi
K
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D000686:Amyloidosis / Q000209:etiology / Q000378:metabolism; D000818:Animals; D016633:Apolipoprotein A-II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002942:Circular Dichroism; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D000682:Amyloid; D016633:Apolipoprotein A-II; D010446:Peptide Fragments