Heterologous Stacking of Prion Protein Peptides Reveals Structural Details of Fibrils and Facilitates Complete Inhibition of Fibril Growth

Fibrils play an important role in the pathogenesis of amyloidosis; however, the underlying mechanisms of the growth process and the structural details of fibrils are poorly understood. Crucial in the fibril formation of prion proteins is the stacking of PrP monomers. We previously proposed that the...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-05, Vol.284 (19), p.12809-12820
Main Authors: Boshuizen, Ronald S., Schulz, Veronica, Morbin, Michela, Mazzoleni, Giulia, Meloen, Rob H., Langedijk, Johannes P.M.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Chromatography, High Pressure Liquid
Cyclization
Dimerization
Humans
Models, Molecular
Molecular Mimicry
Molecular Sequence Data
Nucleotidyltransferases - chemistry
Nucleotidyltransferases - metabolism
Peptide Fragments - chemistry
Peptide Fragments - metabolism
Protein Conformation
PrPSc Proteins - antagonists & inhibitors
PrPSc Proteins - chemistry
PrPSc Proteins - metabolism
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Summary:Fibrils play an important role in the pathogenesis of amyloidosis; however, the underlying mechanisms of the growth process and the structural details of fibrils are poorly understood. Crucial in the fibril formation of prion proteins is the stacking of PrP monomers. We previously proposed that the structure of the prion protein fibril may be similar as a parallel left-handed β-helix. The β-helix is composed of spiraling rungs of parallel β-strands, and in the PrP model residues 105–143 of each PrP monomer can contribute two β-helical rungs to the growing fibril. Here we report data to support this model. We show that two cyclized human PrP peptides corresponding to residues 105–124 and 125–143, based on two single rungs of the left-handed β-helical core of the human PrPSc fibril, show spontaneous cooperative fibril growth in vitro by heterologous stacking. Because the structural model must have predictive value, peptides were designed based on the structure rules of the left-handed β-helical fold that could stack with prion protein peptides to stimulate or to block fibril growth. The stimulator peptide was designed as an optimal left-handed β-helical fold that can serve as a template for fibril growth initiation. The inhibiting peptide was designed to bind to the exposed rung but frustrate the propagation of the fibril growth. The single inhibitory peptide hardly shows inhibition, but the combination of the inhibitory with the stimulatory peptide showed complete inhibition of the fibril growth of peptide huPrP-(106–126). Moreover, the unique strategy based on stimulatory and inhibitory peptides seems a powerful new approach to study amyloidogenic fibril structures in general and could prove useful for the development of therapeutics.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M809151200