KMID : 0578320090270060651
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Molecules and Cells 2009 Volume.27 No. 6 p.651 ~ p.656
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Interaction models of substrate peptides and ¥â-secretase studied by NMR spectroscopy and molecular dynamics simulation
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Lee Jee-Young
Kim Yang-Mee Chae Chi-Bom Kim Jin-Kyoung Lee Sung-Ah
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Abstract
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The formation of ¥â-amyloid peptide (A¥â) is initiated from cleavage of amyloid precursor protein (APP) by a family of protease, ¥á-, ¥â-, and ¥ã-secretase. Sub W, a substrate peptide, consists of 10 amino acids, which are adjacent to the ¥â-cleavage site of wild-type APP, and Sub M is Swedish mutant with double mutations on the left side of the ¥â-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 ¥â-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 ¥â-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 ¥â-secretase (P5-P3¡Ç), 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 ¥â-secretase than Sub W. The two substrate peptides showed different tendency to bind to ¥â-secretase and this information may useful for drug development to treat and prevent Alzheimer¡¯s disease.
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KEYWORD
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¥â-secretase, Alzheimer¡¯s disease, amyloid precursor protein, molecular dynamics simulation, NMR, Swedish mutant
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