scholarly journals BODIPY Dyes as Probes and Sensors to Study Amyloid-β-Related Processes

Biosensors ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 192
Author(s):  
Sergei V. Dzyuba
Keyword(s):  
Small Molecule ◽  
Conformational Changes ◽  
Self Assembly ◽  
Structural Changes ◽  
Photophysical Properties ◽  
Amyloid Β ◽  
Amyloid Formation ◽  
Diverse Range ◽  
Aβ Peptides ◽  
Underlying Mechanisms

Amyloid formation plays a major role in a number of neurodegenerative diseases, including Alzheimer’s disease. Amyloid-β peptides (Aβ) are one of the primary markers associated with this pathology. Aβ aggregates exhibit a diverse range of morphologies with distinct pathological activities. Recognition of the Aβ aggregates by using small molecule-based probes and sensors should not only enhance understanding of the underlying mechanisms of amyloid formation, but also facilitate the development of therapeutic strategies to interfere with amyloid neurotoxicity. BODIPY (boron dipyrrin) dyes are among the most versatile small molecule fluorophores. BODIPY scaffolds could be functionalized to tune their photophysical properties to the desired ranges as well as to adapt these dyes to various types of conditions and environments. Thus, BODIPY dyes could be viewed as unique platforms for the design of probes and sensors that are capable of detecting and tracking structural changes of various Aβ aggregates. This review summarizes currently available examples of BODIPY dyes that have been used to investigate conformational changes of Aβ peptides, self-assembly processes of Aβ, as well as Aβ interactions with various molecules.

scholarly journals Implications of Metal Binding and Asparagine Deamidation for Amyloid Formation

2018 ◽  
Vol 19 (8) ◽  
pp. 2449 ◽  
Author(s):  
Yutaka Sadakane ◽  
Masahiro Kawahara
Keyword(s):  
Conformational Changes ◽  
Posttranslational Modifications ◽  
Self Assembly ◽  
Metal Binding ◽  
Prion Diseases ◽  
Amyloid Formation ◽  
Amyloidogenic Proteins ◽  
Two Factors ◽  
Asparagine Deamidation ◽  
Β Amyloid

Increasing evidence suggests that amyloid formation, i.e., self-assembly of proteins and the resulting conformational changes, is linked with the pathogenesis of various neurodegenerative disorders such as Alzheimer’s disease, prion diseases, and Lewy body diseases. Among the factors that accelerate or inhibit oligomerization, we focus here on two non-genetic and common characteristics of many amyloidogenic proteins: metal binding and asparagine deamidation. Both reflect the aging process and occur in most amyloidogenic proteins. All of the amyloidogenic proteins, such as Alzheimer’s β-amyloid protein, prion protein, and α-synuclein, are metal-binding proteins and are involved in the regulation of metal homeostasis. It is widely accepted that these proteins are susceptible to non-enzymatic posttranslational modifications, and many asparagine residues of these proteins are deamidated. Moreover, these two factors can combine because asparagine residues can bind metals. We review the current understanding of these two common properties and their implications in the pathogenesis of these neurodegenerative diseases.

scholarly journals Estrogens Inhibit Amyloid-β-Mediated Paired Helical Filament-Like Conformation of Tau Through Antioxidant Activity and miRNA 218 Regulation in hTau Mice

2020 ◽  
Vol 77 (3) ◽  
pp. 1339-1351
Author(s):  
Michela Guglielmotto ◽  
Giusi Manassero ◽  
Valeria Vasciaveo ◽  
Marika Venezia ◽  
Massimo Tabaton ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Conformational Changes ◽  
Amyloid Β ◽  
Tau Phosphorylation ◽  
Paired Helical Filament ◽  
Wild Type ◽  
Aβ Peptides ◽  
Biological Sex ◽  
Nanomolar Concentration ◽  
Estradiol Levels

Background: The risk of developing Alzheimer’s disease as well as its progression and severity are known to be different in men and women, and cognitive decline is greater in women than in men at the same stage of disease and could be correlated at least in part on estradiol levels. Objective: In our work we found that biological sex influences the effect of amyloid-β42 (Aβ42) monomers on pathological tau conformational change. Methods: In this study we used transgenic mice expressing the wild-type human tau (hTau) which were subjected to intraventricular (ICV) injections of Aβ peptides in nanomolar concentration. Results: We found that Aβ42 produces pathological conformational changes and hyperphosphorylation of tau protein in male or ovariectomized female mice but not in control females. The treatment of ovariectomized females with estradiol replacement protects against the pathological conformation of tau and seems to be mediated by antioxidant activity as well as the ability to modulate the expression of miRNA 218 linked to tau phosphorylation. Conclusion: Our study indicates that factors as age, reproductive stage, hormone levels, and the interplay with other risk factors should be considered in women, in order to identify the best appropriate therapeutic approach in prevention of cognitive impairment.

Corrigendum to “Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly” [FEBS Lett. 586 (2012) 3991-3995]

FEBS Letters ◽  
2013 ◽  
Vol 587 (9) ◽  
pp. 1452-1452
Author(s):  
Axel Abelein ◽  
Lisa Lang ◽  
Christofer Lendel ◽  
Astrid Gräslund ◽  
Jens Danielsson
Keyword(s):  
Small Molecule ◽  
Self Assembly ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Molecule Interactions

scholarly journals ClpP protease activation results from the reorganization of the electrostatic interaction networks at the entrance pores

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Mark F. Mabanglo ◽  
Elisa Leung ◽  
Siavash Vahidi ◽  
Thiago V. Seraphim ◽  
Bryan T. Eger ◽  
...  
Keyword(s):  
Small Molecule ◽  
Conformational Changes ◽  
Electrostatic Interaction ◽  
Structural Changes ◽  
Structural Heterogeneity ◽  
Interaction Networks ◽  
Structural Basis ◽  
X Ray ◽  
X Ray Crystallography ◽  
Bacterial Cell Death

Abstract Bacterial ClpP is a highly conserved, cylindrical, self-compartmentalizing serine protease required for maintaining cellular proteostasis. Small molecule acyldepsipeptides (ADEPs) and activators of self-compartmentalized proteases 1 (ACP1s) cause dysregulation and activation of ClpP, leading to bacterial cell death, highlighting their potential use as novel antibiotics. Structural changes in Neisseria meningitidis and Escherichia coli ClpP upon binding to novel ACP1 and ADEP analogs were probed by X-ray crystallography, methyl-TROSY NMR, and small angle X-ray scattering. ACP1 and ADEP induce distinct conformational changes in the ClpP structure. However, reorganization of electrostatic interaction networks at the ClpP entrance pores is necessary and sufficient for activation. Further activation is achieved by formation of ordered N-terminal axial loops and reduction in the structural heterogeneity of the ClpP cylinder. Activating mutations recapitulate the structural effects of small molecule activator binding. Our data, together with previous findings, provide a structural basis for a unified mechanism of compound-based ClpP activation.

scholarly journals Transient small molecule interactions kinetically modulate amyloid β peptide self-assembly

FEBS Letters ◽  
2012 ◽  
Vol 586 (22) ◽  
pp. 3991-3995 ◽  
Author(s):  
Axel Abelein ◽  
Lisa Lang ◽  
Christofer Lendel ◽  
Astrid Gräslund ◽  
Jens Danielsson
Keyword(s):  
Small Molecule ◽  
Self Assembly ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Molecule Interactions

scholarly journals Amyloid-Mediated Mechanisms of Membrane Disruption

Biophysica ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 137-156
Author(s):  
Michele F. M. Sciacca ◽  
Carmelo La Rosa ◽  
Danilo Milardi
Keyword(s):  
Self Assembly ◽  
Molecular Mechanisms ◽  
Conformational Transition ◽  
Prion Diseases ◽  
Membrane Damage ◽  
Amyloid Β ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Amyloid Aggregates ◽  
Abnormal Accumulation

Protein aggregation and amyloid formation are pathogenic events underlying the development of an increasingly large number of human diseases named “proteinopathies”. Abnormal accumulation in affected tissues of amyloid β (Aβ) peptide, islet amyloid polypeptide (IAPP), and the prion protein, to mention a few, are involved in the occurrence of Alzheimer’s (AD), type 2 diabetes mellitus (T2DM) and prion diseases, respectively. Many reports suggest that the toxic properties of amyloid aggregates are correlated with their ability to damage cell membranes. However, the molecular mechanisms causing toxic amyloid/membrane interactions are still far to be completely elucidated. This review aims at describing the mutual relationships linking abnormal protein conformational transition and self-assembly into amyloid aggregates with membrane damage. A cross-correlated analysis of all these closely intertwined factors is thought to provide valuable insights for a comprehensive molecular description of amyloid diseases and, in turn, the design of effective therapies.

scholarly journals Discovery of aryl aminothiazole γ-secretase modulators with novel effects on amyloid β-peptide production

2021 ◽  
Author(s):  
Sanjay Bhattarai ◽  
Lei Liu ◽  
Michael S Wolfe
Keyword(s):  
Structural Changes ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Mechanistic Studies ◽  
Parent Molecule ◽  
Aβ Peptides ◽  
Protein Substrate ◽  
New Compounds ◽  
Aβ Production

A series of analogs based on a prototype aryl aminothiazole γ-secretase modulator (GSM) were synthesized and tested for their effects on the profile of 37-to-42-residue amyloid β-peptides (Aβ) generated through processive proteolysis of precursor protein substrate by γ-secretase. Certain substitutions on the terminal aryl D ring resulted in an altered profile of Aβ production compared to that seen with the parent molecule. Small structural changes led to concentration-dependent increases in Aβ37 and Aβ38 production without parallel decreases in their precursors Aβ40 and Aβ42, respectively. The new compounds therefore apparently also stimulate carboxypeptidase trimming of Aβ peptides > 43 residues, providing novel chemical tools for mechanistic studies of processive proteolysis by γ-secretase.

scholarly journals Photocage-initiated time-resolved solution X-ray scattering investigation of protein dimerization

IUCrJ ◽  
2018 ◽  
Vol 5 (6) ◽  
pp. 667-672 ◽  
Author(s):  
Inokentijs Josts ◽  
Stephan Niebling ◽  
Yunyun Gao ◽  
Matteo Levantino ◽  
Henning Tidow ◽  
...  
Keyword(s):  
Small Molecule ◽  
Conformational Changes ◽  
Structural Changes ◽  
Time Resolved ◽  
Protein Dimerization ◽  
X Ray ◽  
Single Turnover ◽  
X Ray Scattering ◽  
Photoactivatable Proteins ◽  
Ray Scattering

This work demonstrates a new method for investigating time-resolved structural changes in protein conformation and oligomerization via photocage-initiated time-resolved X-ray solution scattering by observing the ATP-driven dimerization of the MsbA nucleotide-binding domain. Photocaged small molecules allow the observation of single-turnover reactions of non-naturally photoactivatable proteins. The kinetics of the reaction can be derived from changes in X-ray scattering associated with ATP-binding and subsequent dimerization. This method can be expanded to any small-molecule-driven protein reaction with conformational changes traceable by X-ray scattering where the small molecule can be photocaged.

Stress-Induced Mechanotransduction: Some Preliminaries

2003 ◽  
Author(s):  
Mohammad R. Kaazempur-Mofrad ◽  
Peter J. Mack ◽  
Helene Karcher ◽  
Javad Golji ◽  
Roger G. Kamm
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Structural Changes ◽  
Protein Complexes ◽  
Element Model ◽  
Cytoskeletal Proteins ◽  
Signaling Cascades ◽  
Mechanical Stimuli ◽  
Underlying Mechanisms ◽  
Biochemical Signals

Mechanical stimuli affect nearly every aspect of cellular function, yet the underlying mechanisms of transduction of force into biochemical signals are not clearly understood. One hypothesis is that forces transmitted via individual proteins, either at the site of cell adhesion to its surroundings or within the stress-bearing members of the cytoskeleton, cause conformational changes that change their binding affinity to other intracellular molecules. This altered equilibrium state can subsequently initiate biochemical signaling cascades of produce immediate structural changes. This paper addresses the distribution of forces within the cell resulting from specific mechanical stimuli, computed using a 3-D multi compartment, continuum, viscoelastic finite element model, and uses these to estimate the forces transmitted by individual proteins and protein complexes. These levels of force are compared to those known to produce conformational changes in cytoskeletal proteins, as speculated from magnetocytometry observations and computed by molecular dynamics.

Model membrane size-dependent amyloidogenesis of Alzheimer's amyloid-β peptides

2017 ◽  
Vol 19 (24) ◽  
pp. 16257-16266 ◽  
Author(s):  
Misaki Kinoshita ◽  
Erina Kakimoto ◽  
Mayu S. Terakawa ◽  
Yuxi Lin ◽  
Tatsuya Ikenoue ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Model Membrane ◽  
Amyloid Formation ◽  
Unilamellar Vesicles ◽  
Aβ Peptides ◽  
Size Dependent ◽  
Large Unilamellar Vesicles

We herein report the mechanism of amyloid formation of amyloid-β (Aβ) peptides on small (SUV) and large unilamellar vesicles (LUVs), which consist of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids.

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