Is the binding of beta-amyloid protein to antichymotrypsin in Alzheimer plaques mediated by a beta-strand insertion?
A growing body of experimental evidence demonstrates that the serpin antichymotrypsin plays a regulatory role in Alzheimer plaque physiology by interacting with the 42 residue beta-amyloid protein, and we have used molecular modeling and energy minimization techniques to study this interaction. Based on the unique plasticity of beta-sheet elements in antichymotrypsin (as well as other serpins), we conclude that the interaction of the two proteins is mediated by insertion of the N-terminus of beta-amyloid into beta-sheet C of antichymotrypsin as a pseudo-strand s1C. This beta-strand insertion requires the displacement of native antichymotrypsin strand s1C, which is known to occur partially or completely at different stages of serpin function. Thus, the association of the two proteins in vivo may be facilitated by a particular functional state of the serpin, e.g., the native or protease-complexed state.
Lukacs
C M
CM
Department of Chemistry, University of Pennsylvania, Philadelphia 19104-6323, USA.
Christianson
D W
DW
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation
D016229:Amyloid beta-Peptides; D002918:Chymotrypsin