Serpin acceleration of amyloid fibril formation: a role for accessory proteins.
Protein aggregation underlies an increasing number of human diseases. Recent experiments have shown that the aggregation reaction is exquisitely specific involving particular interactions between non-native proteins. However, aggregation of certain proteins, for example beta-amyloid, in vivo leads to the recruitment of other proteins into the aggregate. Antichymotrypsin, a non-fibril forming protein, is always observed to be associated with beta-amyloid plaques in Alzheimer's sufferers. The role of antichymotrypsin is controversial with studies showing it can either accelerate or inhibit the aggregation reaction. To investigate the role of antichymotrypsin in fibrillogenesis we have studied its interaction with apolipoprotein C-II, a well characterized model system for the study of fibrillogenesis. Our data demonstrate that sub-stoichiometric amounts of antichymotrypsin and its alternate structural forms can dramatically accelerate the aggregation of apolipoprotein C-II, whereas the presence of alpha(1)-antitrypsin, a structural homologue of antichymotrypsin, cannot. Sedimentation velocity experiments show more apolipoprotein C-II fibrils were formed in the presence of antichymotrypsin. Using pull-down assays and immuno-gold labeling we demonstrate an interaction between antichymotrypsin and apolipoprotein C-II fibrils that specifically occurs during fibrillogenesis. Taken together these data demonstrate an interaction between antichymotrypsin and apolipoprotein C-II that accelerates fibrillogenesis and indicates a specific role for accessory proteins in protein aggregation.
Powers
Glenn A
GA
Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
Pham
Chi L L
CL
Pearce
Mary C
MC
Howlett
Geoffrey J
GJ
Bottomley
Stephen P
SP
D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D053304:Apolipoprotein C-II / Q000378:metabolism*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D011487:Protein Conformation; D015843:Serpins / Q000737:chemistry / Q000494:pharmacology*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D053304:Apolipoprotein C-II; D015843:Serpins