Annular protofibrils are a structurally and functionally distinct type of amyloid oligomer.
Amyloid oligomers are believed to play causal roles in several types of amyloid-related neurodegenerative diseases. Several different types of amyloid oligomers have been reported that differ in morphology, size, or toxicity, raising the question of the pathological significance and structural relationships between different amyloid oligomers. Annular protofibrils (APFs) have been described in oligomer preparations of many different amyloidogenic proteins and peptides as ring-shaped or pore-like structures. They are interesting because their pore-like morphology is consistent with numerous reports of membrane-permeabilizing activity of amyloid oligomers. Here we report the preparation of relatively homogeneous preparations of APFs and an antiserum selective for APFs (alphaAPF) compared with prefibrillar oligomers (PFOs) and fibrils. PFOs appear to be precursors for APF formation, which form in high yield after exposure to a hydrophobic-hydrophilic interface. Surprisingly, preformed APFs do not permeabilize lipid bilayers, unlike the precursor PFOs. APFs display a conformation-dependent, generic epitope that is distinct from that of PFOs and amyloid fibrils. Incubation of PFOs with phospholipids vesicles results in a loss of PFO immunoreactivity with a corresponding increase in alphaAPF immunoreactivity, suggesting that lipid vesicles catalyze the conversion of PFOs into APFs. The annular anti-protofibril antibody also recognizes heptameric alpha-hemolysin pores, but not monomers, suggesting that the antibody recognizes an epitope that is specific for a beta barrel structural motif.
Kayed
Rakez
R
Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, USA.
Pensalfini
Anna
A
Margol
Larry
L
Sokolov
Yuri
Y
Sarsoza
Floyd
F
Head
Elizabeth
E
Hall
James
J
Glabe
Charles
C
D020816:Amino Acid Motifs; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000906:Antibodies / Q000737:chemistry*; D000939:Epitopes / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D020836:Protein Structure, Quaternary
D000682:Amyloid; D016229:Amyloid beta-Peptides; D000906:Antibodies; D000939:Epitopes; D008051:Lipid Bilayers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)