Alzheimer's peptide Abeta1-42 binds to two beta-sheets of alpha1-antichymotrypsin and transforms it from inhibitor to substrate.
The serpin alpha1-antichymotrypsin is a major component of brain amyloid plaques in Alzheimer's disease. In vitro alpha1-antichymotrypsin interacts with the Alzheimer's amyloid peptide Abeta1-42 and stimulates both formation and disruption of neurotoxic Abeta1-42 fibrils in a concentration-dependent manner. We have constructed a new hybrid model of the complex between Abeta1-42 and alpha1-antichymotrypsin in which both amino and carboxyl sequences of Abeta1-42 insert into two different beta-sheets of alpha1-antichymotrypsin. We have tested this model and shown experimentally that full-length and amino-terminal segments of Abeta1-42 bind to alpha1-antichymotrypsin as predicted. We also show that Abeta1-42 forms both intra- and intermolecular SDS-stable complexes with alpha1-antichymotrypsin and that the binding of Abeta1-42 to alpha1-antichymotrypsin abolishes the inhibitory activity of the latter and its ability to form stable complex with chymotrypsin. The existence of both inter- as well as intramolecular complexes of Abeta1-42 explains the nonlinear concentration-dependent effects of alpha1-antichymotrypsin on Abeta1-42 fibril formation, which we have reinvestigated here over a broad range of Abeta1-42:alpha1-antichymotrypsin ratios. These data suggest a molecular basis for the distinction between amorphous and fibrillar Abeta1-42 in vivo. The reciprocal effects of Abeta1-42 and alpha1-antichymotrypsin could play a role in the etiology of Alzheimer's disease.
Janciauskiene
S
S
Department of Medicine, University Hospital of Malmo, Lund University, Malmo 20502, Sweden.
Rubin
H
H
Lukacs
C M
CM
Wright
H T
HT
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D000514:alpha 1-Antichymotrypsin / Q000737:chemistry / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D000514:alpha 1-Antichymotrypsin; C115195:amyloid beta-protein (1-11); C075222:amyloid beta-protein (1-42); C115196:amyloid beta-protein (2-9)