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Mol. Cells 2009; 27(6): 651-656

Published online June 30, 2009

https://doi.org/10.1007/s10059-009-0086-z

© The Korean Society for Molecular and Cellular Biology

Interaction Models of Substrate Peptides and?-Secretase Studied by NMR Spectroscopy and Molecular Dynamics Simulation

Jee-Young Lee, Sung-Ah Lee, Jin-Kyoung Kim, Chi-Bom Chae, and Yangmee Kim

Received: January 13, 2009; Revised: April 22, 2009; Accepted: April 22, 2009

Abstract

The formation of ?-amyloid peptide (A?) is initiated from cleavage of amyloid precursor protein (APP) by a family of protease, ?-, ?-, and ?-secretase. Sub W, a substrate peptide, consists of 10 amino acids, which are adjacent to the ?-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 ?-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 ?-secretase and sub-strate 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 ?-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 ?-secretase than Sub W. The two substrate peptides showed different tendency to bind to ?-secretase and this information may useful for drug development to treat and prevent Alzheimer’s disease.

Keywords ?-secretase, Alzheimer’s disease, amyloid precursor protein, molecular dynamics simulation, NMR, Swedish mutant

Article

Research Article

Mol. Cells 2009; 27(6): 651-656

Published online June 30, 2009 https://doi.org/10.1007/s10059-009-0086-z

Copyright © The Korean Society for Molecular and Cellular Biology.

Interaction Models of Substrate Peptides and?-Secretase Studied by NMR Spectroscopy and Molecular Dynamics Simulation

Jee-Young Lee, Sung-Ah Lee, Jin-Kyoung Kim, Chi-Bom Chae, and Yangmee Kim

Received: January 13, 2009; Revised: April 22, 2009; Accepted: April 22, 2009

Abstract

The formation of ?-amyloid peptide (A?) is initiated from cleavage of amyloid precursor protein (APP) by a family of protease, ?-, ?-, and ?-secretase. Sub W, a substrate peptide, consists of 10 amino acids, which are adjacent to the ?-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 ?-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 ?-secretase and sub-strate 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 ?-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 ?-secretase than Sub W. The two substrate peptides showed different tendency to bind to ?-secretase and this information may useful for drug development to treat and prevent Alzheimer’s disease.

Keywords: ?-secretase, Alzheimer’s disease, amyloid precursor protein, molecular dynamics simulation, NMR, Swedish mutant

Mol. Cells
May 31, 2022 Vol.45 No.5, pp. 273~352
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Fe2+ ion depletion-induced expression of BΔGFP at the early stage of leaf development (Choi et al., pp. 294-305).

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