scholarly journals Interference with Amyloid-β Nucleation by Transient Ligand Interaction

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2129 ◽  
Author(s):  
Tao Zhang ◽  
Jennifer Loschwitz ◽  
Birgit Strodel ◽  
Luitgard Nagel-Steger ◽  
Dieter Willbold
Keyword(s):  
Amyloid Β ◽  
Intrinsically Disordered Protein ◽  
Amyloid Β Peptide ◽  
Amino Acid Residues ◽  
Ligand Interaction ◽  
Drug Candidates ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
First Time ◽  
Β Sheet

Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. All-D-peptides consisting solely of D-enantiomeric amino acid residues are interesting drug candidates that combine high binding specificity with high metabolic stability. Here we characterized the interaction between the 12-residue all-D-peptide D3 and Aβ42 monomers, and how the interaction influences Aβ42 aggregation. We demonstrate for the first time that D3 binds to Aβ42 monomers with submicromolar affinities. These two highly unstructured molecules are able to form complexes with 1:1 and other stoichiometries. Further, D3 at substoichiometric concentrations effectively slows down the β-sheet formation and Aβ42 fibrillation by modulating the nucleation process. The study provides new insights into the molecular mechanism of how D3 affects Aβ assemblies and contributes to our knowledge on the interaction between two IDPs.

scholarly journals Clustering of human prion protein and α-synuclein oligomers requires the prion protein N-terminus

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Nadine S. Rösener ◽  
Lothar Gremer ◽  
Michael M. Wördehoff ◽  
Tatsiana Kupreichyk ◽  
Manuel Etzkorn ◽  
...  
Keyword(s):  
Prion Protein ◽  
Amyloid Β ◽  
Intrinsically Disordered Protein ◽  
Molar Ratio ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
N Terminus ◽  
Human Prion Protein ◽  
Intrinsically Disordered Protein Region ◽  
Slow Dissociation

AbstractThe interaction of prion protein (PrP) and α-synuclein (αSyn) oligomers causes synaptic impairment that might trigger Parkinson’s disease and other synucleinopathies. Here, we report that αSyn oligomers (αSynO) cluster with human PrP (huPrP) into micron-sized condensates. Multivalency of αSyn within oligomers is required for condensation, since clustering with huPrP is not observed for monomeric αSyn. The stoichiometry of the heteroassemblies is well defined with an αSyn:huPrP molar ratio of about 1:1. The αSynO−huPrP interaction is of high affinity, signified by slow dissociation. The huPrP region responsible for condensation of αSynO, residues 95−111 in the intrinsically disordered N-terminus, corresponds to the region required for αSynO-mediated cognitive impairment. HuPrP, moreover, achieves co-clustering of αSynO and Alzheimer’s disease-associated amyloid-β oligomers, providing a case of a cross-interaction of two amyloidogenic proteins through an interlinking intrinsically disordered protein region. The results suggest that αSynO-mediated condensation of huPrP is involved in the pathogenesis of synucleinopathies.

scholarly journals Characterization of AMBN I and II Isoforms and Study of Their Ca2+-Binding Properties

2020 ◽  
Vol 21 (23) ◽  
pp. 9293
Author(s):  
Veronika Vetyskova ◽  
Monika Zouharova ◽  
Lucie Bednarova ◽  
Ondřej Vaněk ◽  
Petra Sázelová ◽  
...  
Keyword(s):  
Intrinsically Disordered Protein ◽  
Significant Feature ◽  
Amino Acid Residues ◽  
Binding Properties ◽  
Specific Sequence ◽  
Intrinsically Disordered ◽  
Disordered Protein

Ameloblastin (Ambn) as an intrinsically disordered protein (IDP) stands for an important role in the formation of enamel—the hardest biomineralized tissue commonly formed in vertebrates. The human ameloblastin (AMBN) is expressed in two isoforms: full-length isoform I (AMBN ISO I) and isoform II (AMBN ISO II), which is about 15 amino acid residues shorter than AMBN ISO I. The significant feature of AMBN—its oligomerization ability—is enabled due to a specific sequence encoded by exon 5 present at the N-terminal part in both known isoforms. In this study, we characterized AMBN ISO I and AMBN ISO II by biochemical and biophysical methods to determine their common features and differences. We confirmed that both AMBN ISO I and AMBN ISO II form oligomers in in vitro conditions. Due to an important role of AMBN in biomineralization, we further addressed the calcium (Ca2+)-binding properties of AMBN ISO I and ISO II. The binding properties of AMBN to Ca2+ may explain the role of AMBN in biomineralization and more generally in Ca2+ homeostasis processes.

scholarly journals Determinants for Intrinsically Disordered Protein Recruitment into Phase-Separated Protein Condensates

2022 ◽  
Author(s):  
Yongsang Jo ◽  
Jinyoung Jang ◽  
Daesun Song ◽  
Hyoin Park ◽  
Yongwon Jung
Keyword(s):  
Phase Separation ◽  
Amino Acid ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Amino Acid Residues ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Protein Recruitment ◽  
In Cells

Multivalent interactions between amino acid residues of intrinsically disordered proteins (IDPs) drive phase separation of these proteins into liquid condensates, forming various membrane-less organelles in cells. These interactions between often...

Self-Assembling Micelles Based on an Intrinsically Disordered Protein Domain

2018 ◽  
Author(s):  
Sarah Klass ◽  
Matthew J. Smith ◽  
Tahoe Fiala ◽  
Jessica Lee ◽  
Anthony Omole ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Fusion Proteins ◽  
Organic Molecules ◽  
Intrinsically Disordered Protein ◽  
Protein Domain ◽  
Enzymatic Cleavage ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Self Assembling ◽  
Protein Tag

Herein, we describe a new series of fusion proteins that have been developed to self-assemble spontaneously into stable micelles that are 27 nm in diameter after enzymatic cleavage of a solubilizing protein tag. The sequences of the proteins are based on a human intrinsically disordered protein, which has been appended with a hydrophobic segment. The micelles were found to form across a broad range of pH, ionic strength, and temperature conditions, with critical micelle concentration (CMC) values below 1 µM being observed in some cases. The reported micelles were found to solubilize hydrophobic metal complexes and organic molecules, suggesting their potential suitability for catalysis and drug delivery applications.

scholarly journals Repeated electromagnetic field stimulation lowers amyloid-β peptide levels in primary human mixed brain tissue cultures

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Felipe P. Perez ◽  
Bryan Maloney ◽  
Nipun Chopra ◽  
Jorge J. Morisaki ◽  
Debomoy K. Lahiri
Keyword(s):  
Electromagnetic Field ◽  
Late Onset ◽  
Amyloid Β ◽  
Clinical Settings ◽  
Amyloid Β Peptide ◽  
Field Stimulation ◽  
Amino Acid Residues ◽  
Hyperphosphorylated Tau Protein ◽  
Magnetic Resonance Imaging Mri

AbstractLate Onset Alzheimer’s Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-β (Aβ) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic Aβ levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on Aβ levels (Aβ40 and Aβ42, that are 40 or 42 amino acid residues in length, respectively) in PHB cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro 7 (DIV7) treated with 64 MHz, and 1 hour daily for 14 days (DIV 21) had significantly reduced levels of secreted Aβ40 (p = 001) and Aβ42 (p = 0.029) peptides, compared to untreated cultures. PHB cultures (DIV7) treated at 64 MHz, for 1 or 2 hour during 14 days also produced significantly lower Aβ levels. PHB cultures (DIV28) treated with 64 MHz 1 hour/day during 4 or 8 days produced a similar significant reduction in Aβ40 levels. 0.4 W/kg was the minimum SAR required to produce a biological effect. Exposure did not result in cellular toxicity nor significant changes in secreted Aβ precursor protein-α (sAPPα) levels, suggesting the decrease in Aβ did not likely result from redirection toward the α-secretase pathway. EMF frequency and power used in our work is utilized in human magnetic resonance imaging (MRI, thus suggesting REMFS can be further developed in clinical settings to modulate Aβ deposition.

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