Protein nanofibril design via manipulation of hydrogen bonds

AbstractThe process of amyloid nanofibril formation has broad implications including the generation of the strongest natural materials, namely silk fibers, and their major contribution to the progression of many degenerative diseases. The key question that remains unanswered is whether the amyloidogenic nature, which includes the characteristic H-bonded β-sheet structure and physical characteristics of protein assemblies, can be modified via controlled intervention of the molecular interactions. Here we show that tailored changes in molecular interactions, specifically in the H-bonded network, do not affect the nature of amyloidogenic fibrillation, and even have minimal effect on the initial nucleation events of self-assembly. However, they do trigger changes in networks at a higher hierarchical level, namely enhanced 2D packaging which is rationalized by the 3D hierarchy of β-sheet assembly, leading to variations in fibril morphology, structural composition and, remarkably, nanomechanical properties. These results pave the way to a better understanding of the role of molecular interactions in sculpting the structural and physical properties of protein supramolecular constructs.

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Geometrical frustration as a potential design principle for peptide-based assemblies

Interface Focus ◽

10.1098/rsfs.2016.0141 ◽

2017 ◽

Vol 7 (6) ◽

pp. 20160141 ◽

Cited By ~ 5

Author(s):

Tao Jiang ◽

Elizabeth L. Magnotti ◽

Vincent P. Conticello

Keyword(s):

Self Assembly ◽

Rational Design ◽

Structural Parameters ◽

Two Dimensional ◽

Protein Assemblies ◽

Geometrical Frustration ◽

Protein Motifs ◽

Planar Shapes ◽

And Function

Two-dimensional peptide and protein assemblies have been the focus of increased scientific research as they display significant potential for the creation of functional nanomaterials. Soluble subunits derived from a variety of protein motifs have been demonstrated to self-assemble into structurally defined nanosheets under environmentally benign conditions in which the components often retain their native structure and function. These types of two-dimensional assemblies may have an advantage for nanofabrication in that their extended planar shapes can be more straightforwardly incorporated into the current formats of nanoscale devices. However, significant challenges remain in the fabrication of these materials, particularly in devising methods to control the size, shape and internal structure of the resultant materials. Geometrical frustration may be envisioned as a possible mechanism to exert control over these structural parameters through rational design. While this objective has yet to be realized in practice, we discuss in this article the potential role of geometrical frustration as a principle to rationalize unusual self-assembly behaviour in several examples of two-dimensional peptide assemblies.

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Control over the fibrillization yield by varying the oligomeric nucleation propensities of self-assembling peptides

Communications Chemistry ◽

10.1038/s42004-020-00417-7 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 1

Author(s):

Chun Yin Jerry Lau ◽

Federico Fontana ◽

Laurens D. B. Mandemaker ◽

Dennie Wezendonk ◽

Benjamin Vermeer ◽

...

Keyword(s):

Thermodynamic Stability ◽

Self Assembly ◽

Biomedical Applications ◽

Supramolecular Assemblies ◽

Mechanistic Studies ◽

Molecular Changes ◽

Self Assembling ◽

Charged Residues ◽

Β Sheet

AbstractSelf-assembling peptides are an exemplary class of supramolecular biomaterials of broad biomedical utility. Mechanistic studies on the peptide self-assembly demonstrated the importance of the oligomeric intermediates towards the properties of the supramolecular biomaterials being formed. In this study, we demonstrate how the overall yield of the supramolecular assemblies are moderated through subtle molecular changes in the peptide monomers. This strategy is exemplified with a set of surfactant-like peptides (SLPs) with different β-sheet propensities and charged residues flanking the aggregation domains. By integrating different techniques, we show that these molecular changes can alter both the nucleation propensity of the oligomeric intermediates and the thermodynamic stability of the fibril structures. We demonstrate that the amount of assembled nanofibers are critically defined by the oligomeric nucleation propensities. Our findings offer guidance on designing self-assembling peptides for different biomedical applications, as well as insights into the role of protein gatekeeper sequences in preventing amyloidosis.

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The Inhibitory Effect of Resveratrol on Elastin Amyloidogenesis

Conference Papers in Science ◽

10.1155/2014/410545 ◽

2014 ◽

Vol 2014 ◽

pp. 1-4

Author(s):

Antonietta Pepe ◽

Florian Delaunay ◽

Angelo Bracalello ◽

Brigida Bochicchio

Keyword(s):

Molecular Structure ◽

Atomic Force Microscopy ◽

Self Assembly ◽

Inhibitory Effect ◽

Degenerative Diseases ◽

Force Microscopy ◽

Atomic Force ◽

Circular Dichroïsm

The role of polyphenols in the prevention of degenerative diseases is emerging in the last years. In this report, we will investigate in vitro the inhibitory effect of resveratrol on elastin amyloidogenesis. The effect of resveratrol on molecular structure was investigated by circular dichroism spectroscopy, while the inhibitory effect on self-assembly was evaluated by turbidimetry as a function of temperature and by atomic force microscopy.

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Elucidation of the Self-Assembly Pathway of Lanreotide Octapeptide into β-Sheet Nanotubes: Role of Two Stable Intermediates

Journal of the American Chemical Society ◽

10.1021/ja9088023 ◽

2010 ◽

Vol 132 (12) ◽

pp. 4230-4241 ◽

Cited By ~ 55

Author(s):

Emilie Pouget ◽

Nicolas Fay ◽

Erik Dujardin ◽

Nadège Jamin ◽

Patrick Berthault ◽

...

Keyword(s):

Self Assembly ◽

The Self ◽

Assembly Pathway ◽

Β Sheet

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Role of Side Chains in β-Sheet Self-Assembly into Peptide Fibrils. IR and VCD Spectroscopic Studies of Glutamic Acid-Containing Peptides

Langmuir ◽

10.1021/acs.langmuir.6b00077 ◽

2016 ◽

Vol 32 (18) ◽

pp. 4653-4661 ◽

Cited By ~ 18

Author(s):

Fernando Tobias ◽

Timothy A. Keiderling

Keyword(s):

Glutamic Acid ◽

Self Assembly ◽

Spectroscopic Studies ◽

Side Chains ◽

Peptide Fibrils ◽

Β Sheet

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The Adenomatous polyposis coli tumour suppressor is essential for Axin complex assembly and function and opposes Axin's interaction with Dishevelled

Open Biology ◽

10.1098/rsob.110013 ◽

2011 ◽

Vol 1 (3) ◽

pp. 110013 ◽

Cited By ~ 40

Author(s):

Carolina Mendoza-Topaz ◽

Juliusz Mieszczanek ◽

Mariann Bienz

Keyword(s):

Adenomatous Polyposis Coli ◽

Self Assembly ◽

Wnt Signalling ◽

Tumour Suppressor ◽

Adenomatous Polyposis ◽

Polyposis Coli ◽

Protein Assemblies ◽

Membrane Recruitment ◽

And Function

Most cases of colorectal cancer are linked to mutational inactivation of the Adenomatous polyposis coli (APC) tumour suppressor. APC downregulates Wnt signalling by enabling Axin to promote the degradation of the Wnt signalling effector β-catenin (Armadillo in flies). This depends on Axin's DIX domain whose polymerization allows it to form dynamic protein assemblies (‘degradasomes’). Axin is inactivated upon Wnt signalling, by heteropolymerization with the DIX domain of Dishevelled, which recruits it into membrane-associated ‘signalosomes’. How APC promotes Axin's function is unclear, especially as it has been reported that APC's function can be bypassed by overexpression of Axin. Examining apc null mutant Drosophila tissues, we discovered that APC is required for Axin degradasome assembly, itself essential for Armadillo downregulation. Degradasome assembly is also attenuated in APC mutant cancer cells. Notably, Axin becomes prone to Dishevelled-dependent plasma membrane recruitment in the absence of APC, indicating a crucial role of APC in opposing the interaction of Axin with Dishevelled. Indeed, co-expression experiments reveal that APC displaces Dishevelled from Axin assemblies, promoting degradasome over signalosome formation in the absence of Wnts. APC thus empowers Axin to function in two ways—by enabling its DIX-dependent self-assembly, and by opposing its DIX-dependent copolymerization with Dishevelled and consequent inactivation.

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Studies of the β-sheet mediated self-assembly of designed synthetic peptides of general formula PhCO-Gly-Xx-OCH2Ph and the possible role of aromatic π-π interactions in the self-assembly

ARKIVOC ◽

10.3998/ark.5550190.0010.724 ◽

2009 ◽

Vol 2009 (7) ◽

pp. 247-259 ◽

Cited By ~ 1

Author(s):

Arpita Dutta ◽

Sudeshna Kar ◽

Roland Fröhlich ◽

Pradyot Koley ◽

Animesh Pramanik

Keyword(s):

General Formula ◽

Self Assembly ◽

Synthetic Peptides ◽

The Self ◽

Π Interactions ◽

Β Sheet

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Directive Effect of Chain Length in Modulating Peptide Nano-assemblies

Protein and Peptide Letters ◽

10.2174/0929866527666200224114627 ◽

2020 ◽

Vol 27 (9) ◽

pp. 923-929

Author(s):

Gaurav Pandey ◽

Prem Prakash Das ◽

Vibin Ramakrishnan

Keyword(s):

Electron Microscopy ◽

Amino Acids ◽

Light Scattering ◽

Chain Length ◽

Self Assembly ◽

The Self ◽

Ionic Charge ◽

Self Assembling ◽

Biophysical Techniques

Background: RADA-4 (Ac-RADARADARADARADA-NH2) is the most extensively studied and marketed self-assembling peptide, forming hydrogel, used to create defined threedimensional microenvironments for cell culture applications. Objectives: In this work, we use various biophysical techniques to investigate the length dependency of RADA aggregation and assembly. Methods: We synthesized a series of RADA-N peptides, N ranging from 1 to 4, resulting in four peptides having 4, 8, 12, and 16 amino acids in their sequence. Through a combination of various biophysical methods including thioflavin T fluorescence assay, static right angle light scattering assay, Dynamic Light Scattering (DLS), electron microscopy, CD, and IR spectroscopy, we have examined the role of chain-length on the self-assembly of RADA peptide. Results: Our observations show that the aggregation of ionic, charge-complementary RADA motifcontaining peptides is length-dependent, with N less than 3 are not forming spontaneous selfassemblies. Conclusion: The six biophysical experiments discussed in this paper validate the significance of chain-length on the epitaxial growth of RADA peptide self-assembly.

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