scholarly journals Tandem-Homodimer of a β-Sheet-Forming Short Peptide Inhibits Random-to-β Structural Transition of Its Original Monomer

Processes ◽  
2020 ◽  
Vol 8 (11) ◽  
pp. 1421
Author(s):  
Kin-ya Tomizaki ◽  
Tomomi Iori ◽  
Hideyasu Fukushima ◽  
Yasuhiro Nakabayashi ◽  
Yoshiki Matsumoto ◽  
...  
Keyword(s):  
Amino Acid ◽  
Structural Transition ◽  
Amyloid Β ◽  
Sheet Forming ◽  
Aβ Peptide ◽  
Short Peptide ◽  
New Class ◽  
In Series ◽  
Chain Lengths ◽  
Β Sheet

There is an increasing interest in designing fibrillogenesis modulators for treating amyloid β (Aβ)-peptide-associated diseases. The use of Aβ fragment peptides and their derivatives, as well as nonpeptidyl natural products, is one promising approach to prevent Aβ fibrillation. In this study, we demonstrate that tandem-homodimers (TDs) of a β-sheet-forming short peptide in which the amino acid sequence is duplicated in series and joined via an amino alkanoic acid linker of different chain lengths, preventing the random-to-β structural transition of the original monomer. Ape5-TD, containing 5-amino pentanoate, most potently prevented this transition for at least five days by generating disordered aggregates with reduced tryptic stability. The linkers in the TDs generated this inhibitory activity, probably due to their bent conformations and hydrophobicity, appropriate for accommodating and twisting the monomers, resulting in irregular arrangements of the peptides. The present study could allow the design of a new class of protein/peptide fibrillogenesis modulators.

scholarly journals Effect of the Hydrophilic-Hydrophobic Balance of Antigen-Loaded Peptide Nanofibers on Their Cellular Uptake, Cellular Toxicity, and Immune Stimulatory Properties

2019 ◽  
Vol 20 (15) ◽  
pp. 3781 ◽  
Author(s):  
Tomonori Waku ◽  
Saki Nishigaki ◽  
Yuichi Kitagawa ◽  
Sayaka Koeda ◽  
Kazufumi Kawabata ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Self Assembly ◽  
Sheet Forming ◽  
Design Guidelines ◽  
Cellular Interactions ◽  
Antigenic Peptides ◽  
Peptide Nanofibers ◽  
Dc Line ◽  
Chain Lengths ◽  
Β Sheet

Recently, nanofibers (NFs) formed from antigenic peptides conjugated to β-sheet-forming peptides have attracted much attention as a new generation of vaccines. However, studies describing how the hydrophilic-hydrophobic balance of NF components affects cellular interactions of NFs are limited. In this report, three different NFs were prepared by self-assembly of β-sheet-forming peptides conjugated with model antigenic peptides (SIINFEKL) from ovalbumin and hydrophilic oligo-ethylene glycol (EG) of differing chain lengths (6-, 12- and 24-mer) to investigate the effect of EG length of antigen-loaded NFs on their cellular uptake, cytotoxicity, and dendritic cell (DC)-stimulation ability. We used an immortal DC line, termed JAWS II, derived from bone marrow-derived DCs of a C57BL/6 p53-knockout mouse. The uptake of NFs, consisting of the EG 12-mer by DCs, was the most effective and activated DC without exhibiting significant cytotoxicity. Increasing the EG chain length significantly reduced cellular entry and DC activation by NFs. Conversely, shortening the EG chain enhanced DC activation but increased toxicity and impaired water-dispersibility, resulting in low cellular uptake. These results show that the interaction of antigen-loaded NFs with cells can be tuned by the EG length, which provides useful design guidelines for the development of effective NF-based vaccines.

scholarly journals A photoinduced growth system of peptide nanofibres addressed by DNA hybridization

2015 ◽  
Vol 51 (38) ◽  
pp. 8020-8022 ◽  
Author(s):  
Masahiro Furutani ◽  
Akihito Uemura ◽  
Akira Shigenaga ◽  
Chiaki Komiya ◽  
Akira Otaka ◽  
...  
Keyword(s):  
Amino Acid ◽  
Dna Hybridization ◽  
Sheet Forming ◽  
Growth System ◽  
Spatiotemporal Control ◽  
Β Sheet

Spatiotemporal control of peptide nanofibre growth was achieved by photocleavage of a DNA-conjugated β-sheet-forming peptide with a photoresponsive amino acid.

scholarly journals Amyloid fibrils prepared using an acetylated and methyl amidated peptide model of the α-Synuclein NAC 71–82 amino acid stretch contain an additional cross-β structure also found in prion proteins

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Thomas Näsström ◽  
Per Ola Andersson ◽  
Christian Lejon ◽  
Björn C. G. Karlsson
Keyword(s):  
Amino Acid ◽  
Protein Misfolding ◽  
Prion Proteins ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
Full Length ◽  
Aggregation Propensity ◽  
Amino Acid Stretch ◽  
Amidated Peptide ◽  
Β Sheet

Abstract The 71–82 fragment of the non-amyloid-β component (NAC) region of the Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) related protein α-Synuclein, has been reported to be important during protein misfolding. Although reports have demonstrated the importance of this fragment for the aggregation properties of the full-length protein, its exact role in pre-fibrillar oligomerisation, fibrillar growth and morphology has not yet been fully elucidated. Here, we provide evidence that fibrils prepared from an acetylated and methyl amidated peptide of the NAC 71–82 amino acid stretch of α-Synuclein are amyloid and contain, in addition to the cross-β structure detected in the full-length protein fibrils, a cross-β structure previously observed in prion proteins. These results shed light on the aggregation propensity of the NAC 71–82 amino acid stretch of the full-length protein but also the roles of the N- and C-terminal domains of α-Synuclein in balancing this aggregation propensity. The results also suggest that early aggregated forms of the capped NAC 71–82 peptide generated structures were stabilised by an anti-parallel and twisted β-sheet motif. Due to its expected toxicity, this β-sheet motif may be a promising molecular target for the development of therapeutic strategies for PD and DLB.

scholarly journals A Capped Peptide of the Aggregation Prone NAC 71–82 Amino Acid Stretch of α-Synuclein Folds into Soluble β-Sheet Oligomers at Low and Elevated Peptide Concentrations

2020 ◽  
Vol 21 (5) ◽  
pp. 1629 ◽  
Author(s):  
Thomas Näsström ◽  
Jörgen Ådén ◽  
Fumina Shibata ◽  
Per Ola Andersson ◽  
Björn C.G. Karlsson
Keyword(s):  
Amino Acid ◽  
Prion Proteins ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
Aggregation Kinetics ◽  
Lewy Neurites ◽  
Aggregation Propensity ◽  
Amino Acid Stretch ◽  
Dynamics Simulations ◽  
Β Sheet

Although Lewy bodies and Lewy neurites are hallmarks of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), misfolded α-synuclein oligomers are nowadays believed to be key for the development of these diseases. Attempts to target soluble misfolded species of the full-length protein have been limited so far, probably due to the fast aggregation kinetics and burial of aggregation prone segments in final cross-β-sheet fibrils. A previous characterisation study of fibrils prepared from a capped peptide of the non-amyloid β-component (NAC) 71–82 amino acid stretch of α-synuclein demonstrated an increased aggregation propensity resulting in a cross-β-structure that is also found in prion proteins. From this, it was suggested that capped NAC 71–82 peptide oligomers would provide interesting motifs with a capacity to regulate disease development. Here, we demonstrated, from a series of circular dichroism spectroscopic measurements and molecular dynamics simulations, the molecular-environment-sensitive behaviour of the capped NAC 71–82 peptide in a solution phase and the formation of β-sheet oligomeric structures in the supernatant of a fibrillisation mixture. These results highlighted the use of the capped NAC 71–82 peptide as a motif in the preparation of oligomeric β-sheet structures that potentially could be used in therapeutic strategies in the fight against progressive neurodegenerative disorders, such as PD and DLB.

scholarly journals Anti-Parallel β-Hairpin Structure in Soluble Aβ Oligomers of Aβ40-Dutch and Aβ40-Iowa

2021 ◽  
Vol 22 (3) ◽  
pp. 1225
Author(s):  
Ziao Fu ◽  
William E. Van Nostrand ◽  
Steven O. Smith
Keyword(s):  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Aβ Oligomers ◽  
Dominant Component ◽  
Fibril Structure ◽  
Predominant Component ◽  
Aβ Aggregation ◽  
Aβ Fibrils ◽  
Soluble Aβ Oligomers ◽  
Β Sheet

The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the predominant component of vascular amyloid associated with CAA. There are familial CAA mutations at positions Glu22 and Asp23 that lead to aggressive Aβ aggregation, drive vascular amyloid deposition and result in degradation of vascular membranes. In this study, we compared the transition of the monomeric Aβ40-WT peptide into soluble oligomers and fibrils with the corresponding transitions of the Aβ40-Dutch (E22Q), Aβ40-Iowa (D23N) and Aβ40-Dutch, Iowa (E22Q, D23N) mutants. FTIR measurements show that in a fashion similar to Aβ40-WT, the familial CAA mutants form transient intermediates with anti-parallel β-structure. This structure appears before the formation of cross-β-sheet fibrils as determined by thioflavin T fluorescence and circular dichroism spectroscopy and occurs when AFM images reveal the presence of soluble oligomers and protofibrils. Although the anti-parallel β-hairpin is a common intermediate on the pathway to Aβ fibrils for the four peptides studied, the rate of conversion to cross-β-sheet fibril structure differs for each.

scholarly journals An evaluation of the self-assembly enhancing properties of cell-derived hexameric amyloid-β

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Devkee M. Vadukul ◽  
Céline Vrancx ◽  
Pierre Burguet ◽  
Sabrina Contino ◽  
Nuria Suelves ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Self Assembly ◽  
Critical Nucleus ◽  
Amyloid Fibril ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
The Self ◽  
Aβ Peptide ◽  
Amyloid Fibril Formation ◽  
Secretase Activity

AbstractA key hallmark of Alzheimer’s disease is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide. The Aβ peptide is a product of sequential cleavage of the Amyloid Precursor Protein, the first step of which gives rise to a C-terminal Fragment (C99). Cleavage of C99 by γ-secretase activity releases Aβ of several lengths and the Aβ42 isoform in particular has been identified as being neurotoxic. The misfolding of Aβ leads to subsequent amyloid fibril formation by nucleated polymerisation. This requires an initial and critical nucleus for self-assembly. Here, we identify and characterise the composition and self-assembly properties of cell-derived hexameric Aβ42 and show its assembly enhancing properties which are dependent on the Aβ monomer availability. Identification of nucleating assemblies that contribute to self-assembly in this way may serve as therapeutic targets to prevent the formation of toxic oligomers.

scholarly journals Assessment of Amyloid Forming Tendency of Peptide Sequences from Amyloid Beta and Tau Proteins Using Force-Field, Semi-Empirical, and Density Functional Theory Calculations

2021 ◽  
Vol 22 (6) ◽  
pp. 3244
Author(s):  
Charuvaka Muvva ◽  
Natarajan Arul Murugan ◽  
Venkatesan Subramanian
Keyword(s):  
Force Field ◽  
Density Functional ◽  
Amyloid Β ◽  
Density Functional Theory Calculations ◽  
Tau Proteins ◽  
Functional Theory ◽  
Energy Profiles ◽  
Α Helix ◽  
Semi Empirical ◽  
Β Sheet

A wide variety of neurodegenerative diseases are characterized by the accumulation of protein aggregates in intraneuronal or extraneuronal brain regions. In Alzheimer’s disease (AD), the extracellular aggregates originate from amyloid-β proteins, while the intracellular aggregates are formed from microtubule-binding tau proteins. The amyloid forming peptide sequences in the amyloid-β peptides and tau proteins are responsible for aggregate formation. Experimental studies have until the date reported many of such amyloid forming peptide sequences in different proteins, however, there is still limited molecular level understanding about their tendency to form aggregates. In this study, we employed umbrella sampling simulations and subsequent electronic structure theory calculations in order to estimate the energy profiles for interconversion of the helix to β-sheet like secondary structures of sequences from amyloid-β protein (KLVFFA) and tau protein (QVEVKSEKLD and VQIVYKPVD). The study also included a poly-alanine sequence as a reference system. The calculated force-field based free energy profiles predicted a flat minimum for monomers of sequences from amyloid and tau proteins corresponding to an α-helix like secondary structure. For the parallel and anti-parallel dimer of KLVFFA, double well potentials were obtained with the minima corresponding to α-helix and β-sheet like secondary structures. A similar double well-like potential has been found for dimeric forms for the sequences from tau fibril. Complementary semi-empirical and density functional theory calculations displayed similar trends, validating the force-field based free energy profiles obtained for these systems.

N-(Fluorenyl-9-methoxycarbonyl)amino Acid Amide Derivatives as a New Class of Anti-cancer Agents

2009 ◽  
pp. 465-466 ◽  
Author(s):  
Lajos Gera ◽  
Daniel C. Chan ◽  
Vitalija Simkeviciene ◽  
Paul A. Jr Bunn ◽  
John M. Stewart
Keyword(s):  
Amino Acid ◽  
Acid Amide ◽  
Amino Acid Amide ◽  
New Class ◽  
Amide Derivatives ◽  
Anti Cancer

scholarly journals Compositional Determinants of Prion Formation in Yeast

2009 ◽  
Vol 30 (1) ◽  
pp. 319-332 ◽  
Author(s):  
James A. Toombs ◽  
Blake R. McCarty ◽  
Eric D. Ross
Keyword(s):  
Amino Acid ◽  
Amino Acid Composition ◽  
Amyloid Formation ◽  
Yeast Prion ◽  
Hydrophobic Residues ◽  
Predictive Methods ◽  
Infectious Proteins ◽  
Β Sheet ◽  
Eukaryotic Genomes

ABSTRACT Numerous prions (infectious proteins) have been identified in yeast that result from the conversion of soluble proteins into β-sheet-rich amyloid-like protein aggregates. Yeast prion formation is driven primarily by amino acid composition. However, yeast prion domains are generally lacking in the bulky hydrophobic residues most strongly associated with amyloid formation and are instead enriched in glutamines and asparagines. Glutamine/asparagine-rich domains are thought to be involved in both disease-related and beneficial amyloid formation. These domains are overrepresented in eukaryotic genomes, but predictive methods have not yet been developed to efficiently distinguish between prion and nonprion glutamine/asparagine-rich domains. We have developed a novel in vivo assay to quantitatively assess how composition affects prion formation. Using our results, we have defined the compositional features that promote prion formation, allowing us to accurately distinguish between glutamine/asparagine-rich domains that can form prion-like aggregates and those that cannot. Additionally, our results explain why traditional amyloid prediction algorithms fail to accurately predict amyloid formation by the glutamine/asparagine-rich yeast prion domains.

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