scholarly journals Oxidative Stress Conditions Result in Trapping of PHF-Core Tau (297–391) Intermediates

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 703
Author(s):  
Mahmoud B. Maina ◽  
Youssra K. Al-Hilaly ◽  
Gunasekhar Burra ◽  
Janet E. Rickard ◽  
Charles R. Harrington ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Self Assembly ◽  
Ultra Violet ◽  
Paired Helical Filaments ◽  
The Self ◽  
Cross Linking ◽  
Post Translational Modifications ◽  
Tau Oligomers ◽  
Catalysed Oxidation ◽  
Cross Links

The self-assembly of tau into paired helical filaments (PHFs) in neurofibrillary tangles (NFTs) is a significant event in Alzheimer’s disease (AD) pathogenesis. Numerous post-translational modifications enhance or inhibit tau assembly into NFTs. Oxidative stress, which accompanies AD, induces multiple post-translational modifications in proteins, including the formation of dityrosine (DiY) cross-links. Previous studies have revealed that metal-catalysed oxidation (MCO) using Cu2+ and H2O2 leads to the formation of DiY cross-links in two misfolding proteins, Aβ and α-synuclein, associated with AD and Parkinson’s disease respectively. The effect of MCO on tau remains unknown. Here, we examined the effect of MCO and ultra-violet oxidation to study the influence of DiY cross-linking on the self-assembly of the PHF-core tau fragment. We report that DiY cross-linking facilitates tau assembly into tau oligomers that fail to bind thioflavin S, lack β-sheet structure and prevents their elongation into filaments. At a higher concentration, Cu2+ (without H2O2) also facilitates the formation of these tau oligomers. The DiY cross-linked tau oligomers do not cause cell death. Our findings suggest that DiY cross-linking of pre-assembled tau promotes the formation of soluble tau oligomers that show no acute impact on cell viability.

scholarly journals Oxidative stress conditions result in trapping of PHF-core tau (297-391) intermediates.

2020 ◽  
Author(s):  
Mahmoud Bukar Maina ◽  
Youssra Al-Hilaly ◽  
Gunasekhar Bukar Burra ◽  
Janet Rickard ◽  
Charlie Harrington ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Toxicity ◽  
Self Assembly ◽  
Ultra Violet ◽  
Paired Helical Filaments ◽  
The Self ◽  
Cross Linking ◽  
Post Translational Modifications ◽  
Tau Oligomers ◽  
Cross Links

The self-assembly of tau into paired helical filaments (PHF) in neurofibrillary tangles (NFTs) is a significant event in Alzheimer s disease (AD) pathogenesis. Oxidative stress, which accompanies AD, induces multiple post-translational modifications in proteins including the formation of dityrosine (DiY) cross-links, previously observed for Abeta. Here, metal catalysed- and ultra-violet oxidation were used to study the influence of DiY cross-linking on the self-assembly of the PHF-core tau fragment. We report that DiY cross-linking facilitates tau assembly into tau oligomers and prevents their elongation into filaments. The DiY cross-linked tau oligomers were not toxic to cells. Our findings suggest that DiY cross-linking of pre-assembled tau, promotes the formation of soluble tau oligomers that show no acute toxicity.

scholarly journals Dityrosine cross-link trapping of amyloid-β intermediates reveals that self-assembly is required for Aβ-induced cytotoxicity

2020 ◽  
Author(s):  
Mahmoud B. Maina ◽  
Kurtis Mengham ◽  
Gunasekhar K. Burra ◽  
Youssra A. Al-Hilaly ◽  
Louise C. Serpell
Keyword(s):  
Self Assembly ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Cross Linking ◽  
Wild Type ◽  
Catalysed Oxidation ◽  
Mechanism Of Toxicity ◽  
Cross Links ◽  
Multiple Chemical

AbstractMultiple chemical reactions, such as the production of reactive oxygen species (ROS) can lead to dityrosine (DiY) formation via the cross-linking of closely spaced tyrosine residues and this can serve as a marker for aging. Amyloid-β (Aβ) has been found to be DiY cross-linked in the brains of AD patients. In vitro, Aβ forms DiY cross-links via metal-catalysed oxidation (Cu2+ and H202) (MCO) leading to the formation of fibrils that are resistant to formic acid denaturation. However, copper is well known to influence and enhance self-assembly. Here, to investigate the interplay between self-assembly and DiY cross-linking we have utilised a non-assembly competent variant of Aβ (vAβ). MCO and UV oxidation experiments using vAβ and wild-type Aβ, revealed that DiY cross-linking stabilises, but does not induce or promote Aβ assembly. Cu2+ alone, without H202, facilitates the formation and DiY cross-linking of wild-type Aβ into long-lived oligomers. Our work reveals DiY formation halts further Aβ self-assembly. DiY cross-linked Aβ is non-toxic to neuroblastoma cells at all stages of self-assembly in contrast to oligomeric non-cross-linked Aβ. These findings point to a mechanism of toxicity that necessitates continuing self-assembly of the Aβ peptide, whereby trapped DiY Aβ assemblies and assembly incompetent variant Aβ are unable to result in cell death.

scholarly journals Cross-linking reveals laminin coiled-coil architecture

2016 ◽  
Vol 113 (47) ◽  
pp. 13384-13389 ◽  
Author(s):  
Gad Armony ◽  
Etai Jacob ◽  
Toot Moran ◽  
Yishai Levin ◽  
Tevie Mehlman ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Self Assembly ◽  
Quaternary Structure ◽  
Coiled Coil ◽  
Surface Proteins ◽  
Cross Linking ◽  
Single Particle Reconstruction ◽  
Cross Links ◽  
Particle Reconstruction ◽  
Key Questions

Laminin, an ∼800-kDa heterotrimeric protein, is a major functional component of the extracellular matrix, contributing to tissue development and maintenance. The unique architecture of laminin is not currently amenable to determination at high resolution, as its flexible and narrow segments complicate both crystallization and single-particle reconstruction by electron microscopy. Therefore, we used cross-linking and MS, evaluated using computational methods, to address key questions regarding laminin quaternary structure. This approach was particularly well suited to the ∼750-Å coiled coil that mediates trimer assembly, and our results support revision of the subunit order typically presented in laminin schematics. Furthermore, information on the subunit register in the coiled coil and cross-links to downstream domains provide insights into the self-assembly required for interaction with other extracellular matrix and cell surface proteins.

scholarly journals Supramolecular self-assembly of a polyelectrolyte chain based on step-growth polymerization of hydrophobic and hydrophilic monomers

RSC Advances ◽  
2017 ◽  
Vol 7 (83) ◽  
pp. 52832-52840
Author(s):  
Li Sun ◽  
Shang Ma ◽  
Chen Wang ◽  
Yongmei Chi ◽  
Jian Dong
Keyword(s):  
Citric Acid ◽  
Self Assembly ◽  
The Self ◽  
Hexamethylene Diisocyanate ◽  
Cross Linking ◽  
Polyelectrolyte Chain ◽  
Step Growth ◽  
Step Growth Polymerization ◽  
Hydrophilic Monomers

Polymerization of citric acid and hexamethylene diisocyanate and hydrolysis results in a polyelectrolyte PHMC. Noncovalent cross-linking of cooperative H-bonding units stabilizes the self-assembly of the PHMC chains into nanoparticles in water.

Self-assembly of graphene oxide aerogels by layered double hydroxides cross-linking and their application in water purification

2014 ◽  
Vol 2 (23) ◽  
pp. 8941-8951 ◽  
Author(s):  
Qile Fang ◽  
Baoliang Chen
Keyword(s):  
Graphene Oxide ◽  
Structural Stability ◽  
Water Purification ◽  
Layered Double Hydroxides ◽  
Self Assembly ◽  
Adsorption Properties ◽  
The Self ◽  
Cross Linking ◽  
Double Hydroxides

3D macrostructural aerogels were synthesized based on the self-assembly of graphene oxide and LDHs, which exhibited excellent hydrophilicity, structural stability, and superior adsorption properties in water purification.

Cross-Linking Density and Temperature Effects on the Self-Assembly of SiO2-PNIPAAm Core-Shell Particles at Interfaces

2013 ◽  
Vol 19 (18) ◽  
pp. 5586-5594 ◽  
Author(s):  
Kadriye Özlem Nazli ◽  
Christian W. Pester ◽  
Artjom Konradi ◽  
Alexander Böker ◽  
Patrick van Rijn
Keyword(s):  
Self Assembly ◽  
Temperature Effects ◽  
The Self ◽  
Cross Linking ◽  
Core Shell ◽  
Shell Particles

Inside Cover: Cross-Linking Density and Temperature Effects on the Self-Assembly of SiO2-PNIPAAm Core-Shell Particles at Interfaces (Chem. Eur. J. 18/2013)

2013 ◽  
Vol 19 (18) ◽  
pp. 5498-5498
Author(s):  
Kadriye Özlem Nazli ◽  
Christian W. Pester ◽  
Artjom Konradi ◽  
Alexander Böker ◽  
Patrick van Rijn
Keyword(s):  
Self Assembly ◽  
Temperature Effects ◽  
The Self ◽  
Cross Linking ◽  
Core Shell ◽  
Shell Particles

scholarly journals Elastin as a self–organizing biomaterial: use of recombinantly expressed human elastin polypeptides as a model for investigations of structure and self–assembly of elastin

2002 ◽  
Vol 357 (1418) ◽  
pp. 185-189 ◽  
Author(s):  
F. W. Keeley ◽  
C. M. Bellingham ◽  
K. A. Woodhouse
Keyword(s):  
Self Assembly ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Cross Linking ◽  
Sufficient Information ◽  
Elastic Recoil ◽  
Membrane Structures ◽  
Self Assembling ◽  
Cross Links ◽  
Organizational Ability

Elastin is the major extracellular matrix protein of large arteries such as the aorta, imparting characteristics of extensibility and elastic recoil. Once laid down in tissues, polymeric elastin is not subject to turnover, but is able to sustain its mechanical resilience through thousands of millions of cycles of extension and recoil. Elastin consists of ca . 36 domains with alternating hydrophobic and cross–linking characteristics. It has been suggested that these hydrophobic domains, predominantly containing glycine, proline, leucine and valine, often occurring in tandemly repeated sequences, are responsible for the ability of elastin to align monomeric chains for covalent cross–linking. We have shown that small, recombinantly expressed polypeptides based on sequences of human elastin contain sufficient information to self–organize into fibrillar structures and promote the formation of lysine–derived cross–links. These cross–linked polypeptides can also be fabricated into membrane structures that have solubility and mechanical properties reminiscent of native insoluble elastin. Understanding the basis of the self–organizational ability of elastin–based polypeptides may provide important clues for the general design of self–assembling biomaterials.

scholarly journals Supramolecular Functionalizable Linear–Dendritic Block Copolymers for the Preparation of Nanocarriers by Microfluidics

Polymers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 684 ◽  
Author(s):  
Miriam Abad ◽  
Alejandro Martínez-Bueno ◽  
Gracia Mendoza ◽  
Manuel Arruebo ◽  
Luis Oriol ◽  
...  
Keyword(s):  
Block Copolymers ◽  
Self Assembly ◽  
The Self ◽  
Cross Linking ◽  
Spectroscopic Techniques ◽  
Polymeric Nanocarriers ◽  
Transmission Electron ◽  
Click Coupling ◽  
Drug Nanocarriers ◽  
Fast Synthesis

Hybrid linear–dendritic block copolymers (LDBCs) having dendrons with a precise number of peripheral groups that are able to supramolecular bind functional moieties are challenging materials as versatile polymeric platforms for the preparation of functional polymeric nanocarriers. PEG2k-b-dxDAP LDBCs that are based on polyethylene glycol (PEG) as hydrophilic blocks and dendrons derived from bis-MPA having 2,6-diacylaminopyridine (DAP) units have been efficiently synthesized by the click coupling of preformed blocks, as was demonstrated by spectroscopic techniques and mass spectrometry. Self-assembly ability was first checked by nanoprecipitation. A reproducible and fast synthesis of aggregates was accomplished by microfluidics optimizing the total flow rate and phase ratio to achieve spherical micelles and/or vesicles depending on dendron generation and experimental parameters. The morphology and size of the self-assemblies were studied by TEM, Cryogenic Transmission Electron Microscopy (cryo-TEM), and Dynamic Light Scattering (DLS). The cytotoxicity of aggregates synthesized by microfluidics and the influence on apoptosis and cell cycle evaluation was studied on four cell lines. The self-assemblies are not cytotoxic at doses below 0.4 mg mL−1. Supramolecular functionalization using thymine derivatives was explored for reversibly cross-linking the hydrophobic blocks. The results open new possibilities for their use as drug nanocarriers with a dynamic cross-linking to improve nanocarrier stability but without hindering disassembly to release molecular cargoes.

scholarly journals Assembly and Covalent Cross-Linking of an Amine-Functionalised Metal-Organic Cage

2021 ◽  
Vol 9 ◽  
Author(s):  
Matthew L. Schneider ◽  
Adrian W. Markwell-Heys ◽  
Oliver M. Linder-Patton ◽  
Witold M. Bloch
Keyword(s):  
Functional Groups ◽  
Self Assembly ◽  
Metal Organic Framework ◽  
The Self ◽  
Porous Solids ◽  
Cross Linking ◽  
Two Dimensional ◽  
Amine Functionalized ◽  
Metal Organic ◽  
Organic Framework

The incorporation of reactive functional groups onto the exterior of metal-organic cages (MOCs) opens up new opportunities to link their well-defined scaffolds into functional porous solids. Amine moieties offer access to a rich catalogue of covalent chemistry; however, they also tend to coordinate undesirably and interfere with MOC formation, particular in the case of Cu2 paddlewheel-based MOCs. We demonstrate that tuning the basicity of an aniline-functionalized ligand enables the self-assembly of a soluble, amine-functionalized Cu4L4 lantern cage (1). Importantly, we show control over the coordinative propensity of the exterior amine of the ligand, which enables us to isolate a crystalline, two-dimensional metal-organic framework composed entirely of MOC units (2). Furthermore, we show that the nucleophilicity of the exterior amine of 1 can be accessed in solution to generate a cross-linked cage polymer (3) via imine condensation.

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