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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
Dec 31, 2021 Vol.44 No.12, pp. 861~919
COVER PICTURE
Structure of the fly peripheral neurons in the fly head. Flies have basic sensory organs including eyes for vision, antennae and maxillary palps for olfaction, and proboscis (magenta) for gustation which can be labelled with monoclonal antibody 22C10. The figure is a 3D reconstructed image with 30 slices of confocal sections with 3 μm interval. It shows that the proboscis is required for sensing attractive carboxylic acids such as glycolic acid, citric acid, and lactic acid (Shrestha and Lee, pp. 900-910).

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