Interaction models of substrate peptides and [beta]-secretase studied by NMR spectroscopy and molecular dynamics simulation

The formation of β-amyloid peptide (Aβ) is initiated from cleavage of amyloid precursor protein (APP) by a family of protease, α-, β-, and γ-secretase. Sub W, a substrate peptide, consists of 10 amino acids, which are adjacent to the β-cleavage site of wild-type APP, and Sub M is Swedish mutant with...

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Bibliographic Details
Published in:Molecules and cells 2009-06, Vol.27 (6), p.651
Main Authors: Lee, Jee-young, Lee, Sung-ah, Kim, Jin-kyoung, Chae, Chi-bom, Kim, Yangmee
Format: Article
Language:English
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Summary:The formation of β-amyloid peptide (Aβ) is initiated from cleavage of amyloid precursor protein (APP) by a family of protease, α-, β-, and γ-secretase. Sub W, a substrate peptide, consists of 10 amino acids, which are adjacent to the β-cleavage site of wild-type APP, and Sub M is Swedish mutant with double mutations on the left side of the β-cleavage site of APP. Sub W is a normal product of the metabolism of APP in the secretary pathway. Sub M is known to increase the efficiency of β-secretase activity, resulting in a more specific binding model compared to Sub W. Three-dimensional structures of Sub W and Sub M were studied by CD and NMR spectroscopy in water solution. On the basis of these structures, interaction models of β-secretase and substrate peptides were determined by molecular dynamics simulation. Four hydrogen bonds and one water-mediated interaction were formed in the docking models. In particular, the hydrogen bonding network of Sub M-BACE formed spread over the broad region of the active site of β-secretase (P5-P3'), and the side chain of P2-Asn formed a hydrogen bond specifically with the side chain of Arg235. These are more favorable to the cleavage of Sub M by β-secretase than Sub W. The two substrate peptides showed different tendency to bind to β-secretase and this information may useful for drug development to treat and prevent Alzheimer's disease.
ISSN:1016-8478
0219-1032
DOI:10.1007/s10059-009-0086-z