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Title: Molecular Self-Assembly Strategy for Generating Catalytic Hybrid Polypeptides

Abstract

Recently, catalytic peptides were introduced that mimicked protease activities and showed promising selectivity of products even in organic solvents where protease cannot perform well. However, their catalytic efficiency was extremely low compared to natural enzyme counterparts presumably due to the lack of stable tertiary fold. We hypothesized that assembling these peptides along with simple hydrophobic pockets, mimicking enzyme active sites, could enhance the catalytic activity. Here we fused the sequence of catalytic peptide CP4, capable of protease and esterase-like activities, into a short amyloidogenic peptide fragment of Aβ. When the fused CP4-Aβ construct assembled into antiparallel β- sheets and amyloid fibrils, a 4.0-fold increase in the hydrolysis rate of p-nitrophenyl acetate (p-NPA) compared to neat CP4 peptide was observed. Furthermore, the enhanced catalytic activity of CP4-Aβ assembly could be explained both by pre-organization of a catalytically competent Ser-His-acid triad and hydrophobic stabilization of a bound substrate between the triad and p-NPA, indicating that a design strategy for self-assembled peptides is important to accomplish the desired functionality.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
City of New York Research Foundation
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1346601
Alternate Identifier(s):
OSTI ID: 1258450
Grant/Contract Number:  
FG-02-01ER45935; FG02-01ER45935
Resource Type:
Published Article
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Name: PLoS ONE Journal Volume: 11 Journal Issue: 4; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science (PLoS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; polypeptides; peptides; hydrolysis; sequence motif analysis; molecular dynamics; proteases; sequence assembly tools; amyloid proteins

Citation Formats

Maeda, Yoshiaki, Fang, Justin, Ikezoe, Yasuhiro, Pike, Douglas H., Nanda, Vikas, Matsui, Hiroshi, and Xu, ed., Bing. Molecular Self-Assembly Strategy for Generating Catalytic Hybrid Polypeptides. United States: N. p., 2016. Web. doi:10.1371/journal.pone.0153700.
Maeda, Yoshiaki, Fang, Justin, Ikezoe, Yasuhiro, Pike, Douglas H., Nanda, Vikas, Matsui, Hiroshi, & Xu, ed., Bing. Molecular Self-Assembly Strategy for Generating Catalytic Hybrid Polypeptides. United States. doi:10.1371/journal.pone.0153700.
Maeda, Yoshiaki, Fang, Justin, Ikezoe, Yasuhiro, Pike, Douglas H., Nanda, Vikas, Matsui, Hiroshi, and Xu, ed., Bing. Tue . "Molecular Self-Assembly Strategy for Generating Catalytic Hybrid Polypeptides". United States. doi:10.1371/journal.pone.0153700.
@article{osti_1346601,
title = {Molecular Self-Assembly Strategy for Generating Catalytic Hybrid Polypeptides},
author = {Maeda, Yoshiaki and Fang, Justin and Ikezoe, Yasuhiro and Pike, Douglas H. and Nanda, Vikas and Matsui, Hiroshi and Xu, ed., Bing},
abstractNote = {Recently, catalytic peptides were introduced that mimicked protease activities and showed promising selectivity of products even in organic solvents where protease cannot perform well. However, their catalytic efficiency was extremely low compared to natural enzyme counterparts presumably due to the lack of stable tertiary fold. We hypothesized that assembling these peptides along with simple hydrophobic pockets, mimicking enzyme active sites, could enhance the catalytic activity. Here we fused the sequence of catalytic peptide CP4, capable of protease and esterase-like activities, into a short amyloidogenic peptide fragment of Aβ. When the fused CP4-Aβ construct assembled into antiparallel β- sheets and amyloid fibrils, a 4.0-fold increase in the hydrolysis rate of p-nitrophenyl acetate (p-NPA) compared to neat CP4 peptide was observed. Furthermore, the enhanced catalytic activity of CP4-Aβ assembly could be explained both by pre-organization of a catalytically competent Ser-His-acid triad and hydrophobic stabilization of a bound substrate between the triad and p-NPA, indicating that a design strategy for self-assembled peptides is important to accomplish the desired functionality.},
doi = {10.1371/journal.pone.0153700},
journal = {PLoS ONE},
number = 4,
volume = 11,
place = {United States},
year = {2016},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1371/journal.pone.0153700

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