Enzymatically triggered amyloid formation: an approach for studying peptide aggregation

Broncel, Malgorzata; Wagner, Sara C.; Hackenberger, Christian P. R.; Koksch, Beate

doi:10.1039/c001460e

Cited by 17 publications

(15 citation statements)

References 18 publications

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“…To summarize this previous work, we were able to design model peptides that adopted different conformations and aggregate morphologies depending on the concentration, pH, ionic strength, and the presence of metal ions or other triggers. [46][47][48][49][50] Our earlier success in the rational design of amyloidogenic model peptides encouraged us to investigate strategies to inhibit aggregation. As discussed in detail above, one promising approach is the preclusion of amyloid formation by stabilization of the helical conformation of a target peptide through the formation of stable assemblies.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Amyloid Aggregation by Formation of Helical Assemblies

Brandenburg

Berlepsch

Gerling

et al. 2011

Chemistry A European J

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The formation of amyloid aggregates is responsible for a wide range of diseases, including Alzheimer's and Parkinson's disease. Although the amyloid-forming proteins have different structures and sequences, all undergo a conformational change to form amyloid aggregates that have a characteristic cross-β-structure. The mechanistic details of this process are poorly understood, but different strategies for the development of inhibitors of amyloid formation have been proposed. In most cases, chemically diverse compounds bind to an elongated form of the protein in a β-strand conformation and thereby exert their therapeutic effect. However, this approach could favor the formation of prefibrillar oligomeric species, which are thought to be toxic. Herein, we report an alternative approach in which a helical coiled-coil-based inhibitor peptide has been designed to engage a coiled-coil-based amyloid-forming model peptide in a stable coiled-coil arrangement, thereby preventing rearrangement into a β-sheet conformation and the subsequent formation of amyloid-like fibrils. Moreover, we show that the helix-forming peptide is able to disassemble mature amyloid-like fibrils.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Amyloid Aggregation by Formation of Helical Assemblies

Brandenburg

Berlepsch

Gerling

et al. 2011

Chemistry A European J

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“…Further, this allows one to exploit the enzymatic action of phosphatase to trigger the formation of fibrillar hydrogel, which depends on the ability of the peptide to access its thermodynamic minimum on the energy folding landscape. Although there are elegant reports of using dephosphorylation or phosphorylation events to study amyloid formation[6], silk modification,[7] and to trigger the hydrogelation of small linear peptides,[8] these employ phosphorylated residues to endear water solubility to the peptide; when removed, aqueous buffer becomes a poor solvent and the peptides assemble in response. Herein, we exploit phosphorylation to control the folded conformation of peptides, which is energetically coupled to their ability to form supramolecular assemblies.…”

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confidence: 99%

Enzymatic Control of the Conformational Landscape of Self‐Assembling Peptides

2018

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Post-translational modification is a common mechanism to affect conformational change in proteins, which in turn, regulates function. Herein, this principle is expanded to instruct the formation of supramolecular assemblies by controlling the conformational bias of self-assembling peptides. Biophysical and mechanical studies show that an engineered phosphorylation/dephosphorylation couple can affectively modulate the folding of amphiphilic peptides into a conformation necessary for the formation of well-defined fibrillar networks. Negative design principles based on the incompatibility of hosting residue side-chain point charge within hydrophobic environments proved key to inhibiting the peptide's ability to adopt its low energy fold in the assembled state. Dephosphorylation relieves this restriction, lowers the energy barrier between unfolded and folded peptide, and allows the formation of self-assembled fibrils that contain the folded conformer, thus ultimately enabling the formation of a cytocompatible hydrogel material.

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“…In related work, Broncel et al demonstrated that a synthetically phosphorylated amyloidogenic peptide underwent a complex phosphatase-triggered structural transition starting from a random coil and ending in a nanofiber-generating β-sheet conformation. 75 These approaches may prove useful in screening for drugs to combat Alzheimer’s disease and other related amyloidopathies, as well as aiding in the understanding of the basic biochemical underpinnings of amyloid pathology. 76,77 …”

Section: Enzyme-driven Assembly Of Supramolecular Fibrilsmentioning

confidence: 99%

Enzyme-directed assembly and manipulation of organic nanomaterials

Hahn

Gianneschi

2011

Chem. Commun.

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Enzymes are the prime protagonists in the chemistry of living organisms. As such, chemists and biologists have long been fascinated by the array of highly selective transformations possible under biological conditions that are facilitated by enzymecatalyzed reactions. Moreover, enzymes are involved in replicating, repairing and transmitting information in a highly selective and organized fashion through detection and signal amplification cascades. Indeed, because of their selectivity and potential for use outside of biological systems, enzymes have found immense utility in various biochemical assays and are increasingly finding applications in the preparation of small molecules. By contrast, the use of enzymatic reactions to prepare and build supramolecular and nanoscale materials is relatively rare. In this article, we seek to highlight efforts over the past 10 years at taking advantage of enzymatic reactions to assemble and manipulate complex soft, organic materials on the nanoscale. It is tantalizing to think of these processes as mimics of natural systems where enzymes are used in the assembly and transformation of the most complex nanomaterials known, for example, virus capsid assemblies and the myriad array of nanoscale biomolecular machinery.

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Enzymatically triggered amyloid formation: an approach for studying peptide aggregation

Abstract: A strategy has been demonstrated that utilizes a phosphatase as a natural tool for the triggering and control of amyloid formation in a coiled coil peptide model under conditions that closely approximate a physiological environment.

Cited by 17 publications

References 18 publications

Inhibition of Amyloid Aggregation by Formation of Helical Assemblies

Inhibition of Amyloid Aggregation by Formation of Helical Assemblies

Enzymatic Control of the Conformational Landscape of Self‐Assembling Peptides

Enzyme-directed assembly and manipulation of organic nanomaterials

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