Molecular Self-Assembly Strategy for Generating Catalytic Hybrid Polypeptides.
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. 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.
Department of Chemistry, Hunter College and the Graduate Center, City University of New York, New York, New York, United State of America.
Yoshiaki
Y
Maeda
Department of Chemistry, Hunter College and the Graduate Center, City University of New York, New York, New York, United State of America.
Justin
J
Fang
Department of Chemistry, Hunter College and the Graduate Center, City University of New York, New York, New York, United State of America.
Yasuhiro
Y
Ikezoe
Department of Biochemistry, Center for Advanced Biotechnology and Medicine and the Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United State of America.
Douglas H
DH
Pike
Department of Biochemistry, Center for Advanced Biotechnology and Medicine and the Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United State of America.
Vikas
V
Nanda
Department of Chemistry, Hunter College and the Graduate Center, City University of New York, New York, New York, United State of America.|Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, United State of America.
Hiroshi
H
Matsui
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry; D002384:Catalysis; D020134:Catalytic Domain; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D055503:Protein Multimerization; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000737:chemistry
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins