Seeding specificity in amyloid growth induced by heterologous fibrils.
Over residues 15-36, which comprise the H-bonded core of the amyloid fibrils it forms, the Alzheimer's disease plaque peptide amyloid beta (Abeta) possesses a very similar sequence to that of another short, amyloidogenic peptide, islet amyloid polypeptide (IAPP). Using elongation rates to quantify seeding efficiency, we inquired into the relationship between primary sequence similarity and seeding efficiency between Abeta-(1-40) and amyloid fibrils produced from IAPP as well as other proteins. In both a solution phase and a microtiter plate elongation assay, IAPP fibrils are poor seeds for Abeta-(1-40) elongation, exhibiting weight-normalized efficiencies of only 1-2% compared with Abeta-(1-40) fibrils. Amyloid fibrils of peptides with sequences completely unrelated to Abeta also exhibit poor to negligible seeding ability for Abeta elongation. Fibrils from a number of point mutants of Abeta-(1-40) exhibit intermediate seeding abilities for wild-type Abeta elongation, with differing efficiencies depending on whether or not the mutation is in the amyloid core region. The results suggest that amyloid fibrils from different proteins exhibit structural differences that control seeding efficiencies. Preliminary results also suggest that identical sequences can grow into different conformations of amyloid fibrils as detected by seeding efficiencies. The results have a number of implications for amyloid structure and biology.
O'Nuallain
Brian
B
Graduate School of Medicine, University of Tennessee, Knoxville, Tennessee 37920, USA.
Williams
Angela D
AD
Westermark
Per
P
Wetzel
Ronald
R
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D052160:Benzothiazoles; D019921:Biotinylation; D002455:Cell Division; D002851:Chromatography, High Pressure Liquid; D004396:Coloring Agents / Q000494:pharmacology; D003224:Congo Red / Q000494:pharmacology; D006801:Humans; D058228:Islet Amyloid Polypeptide; D007700:Kinetics; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D017354:Point Mutation; D011108:Polymers / Q000737:chemistry; D017434:Protein Structure, Tertiary; D013844:Thiazoles / Q000737:chemistry; D013997:Time Factors
D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D004396:Coloring Agents; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D011108:Polymers; D013844:Thiazoles; C009462:thioflavin T; D003224:Congo Red