The serpin α1-antichymotrypsin is a major component of brain amyloid plaques in Alzheimer's disease. In vitro α1-antichymotrypsin interacts with the Alzheimer's amyloid peptide Aβ1-42 and stimulates both formation and disruption of neurotoxic Aβ1-42 fibrils in a concentration-dependent manner. We have constructed a new hybrid model of the complex between Aβ1-42 and α1-antichymotrypsin in which both amino and carboxyl sequences of Aβ1-42 insert into two different β-sheets of α1-antichymotrypsin. We have tested this model and shown experimentally that full-length and amino- terminal segments of Aβ1-42 bind to α1-antichymotrypsin as predicted. We also show that Aβ1-42 forms both intra-and intermolecular SDS-stable complexes with α1-antichymotrypsin and that the binding of Aβ1-42 to α1-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 Aβ1-42 explains the nonlinear concentration-dependent effects of α1-antichymotrypsin on Aβ1-42 fibril formation, which we have reinvestigated here over a broad range of Aβ1-42:α1-antichymotrypsin ratios. These data suggest a molecular basis for the distinction between amorphous and fibrillar Aβ1-42 in vivo. The reciprocal effects of Aβ1-42 and α1-antichymotrypsin could play a role in the etiology of Alzheimer's disease.
CITATION STYLE
Janciauskiene, S., Rubin, H., Lukacs, C. M., & Wright, H. T. (1998). Alzheimer’s peptide Aβ1-42 binds to two β-sheets of α1- antichymotrypsin and transforms it from inhibitor to substrate. Journal of Biological Chemistry, 273(43), 28360–28364. https://doi.org/10.1074/jbc.273.43.28360
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