Derivatizing Merocyanine Dyes to Balance Their Polarity and Viscosity Sensitivities for Protein Aggregation Detection

2021 ◽  
Author(s):  
Yulong Bai ◽  
Yanan Huang ◽  
Wang Wan ◽  
Wenhan Jin ◽  
Di Shen ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Misfolding ◽  
Aggregation Process ◽  
Merocyanine Dyes ◽  
Protein Misfolding And Aggregation

Protein misfolding and aggregation process involves local polarity and viscosity fluctuation. Herein we modulated the polarity and viscosity sensitivities of merocyanine dyes to detect protein aggregation. We demonstrated how structural...

scholarly journals Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lars Plate ◽  
Christina B Cooley ◽  
John J Chen ◽  
Ryan J Paxman ◽  
Ciara M Gallagher ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Small Molecule ◽  
Protein Misfolding ◽  
Transcriptional Profiling ◽  
Extracellular Protein ◽  
Unfolded Protein ◽  
Amyloidogenic Proteins ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Protein Misfolding And Aggregation

Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. The ER reprogramming afforded by our molecules requires activation of endogenous ATF6 and occurs independent of global ER stress. Furthermore, our molecules phenocopy the ability of genetic ATF6 activation to selectively reduce secretion and extracellular aggregation of amyloidogenic proteins. These results show that small molecule-dependent ER reprogramming, achieved through preferential activation of the ATF6 transcriptional program, is a promising strategy to ameliorate imbalances in ER function associated with degenerative protein aggregation diseases.

scholarly journals Vibrational Approach to the Dynamics and Structure of Protein Amyloids

Molecules ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 186 ◽  
Author(s):  
Haoqian Li ◽  
Richard Lantz ◽  
Deguo Du
Keyword(s):  
Protein Aggregation ◽  
Unnatural Amino Acids ◽  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Structural Characteristics ◽  
Conformational Dynamics ◽  
Structural Features ◽  
Protein Oligomerization ◽  
Human Pathology ◽  
Protein Misfolding And Aggregation

Amyloid diseases, including neurodegenerative diseases such as Alzheimer’s and Parkinson’s, are linked to a poorly understood progression of protein misfolding and aggregation events that culminate in tissue-selective deposition and human pathology. Elucidation of the mechanistic details of protein aggregation and the structural features of the aggregates is critical for a comprehensive understanding of the mechanisms of protein oligomerization and fibrillization. Vibrational spectroscopies, such as Fourier transform infrared (FTIR) and Raman, are powerful tools that are sensitive to the secondary structure of proteins and have been widely used to investigate protein misfolding and aggregation. We address the application of the vibrational approaches in recent studies of conformational dynamics and structural characteristics of protein oligomers and amyloid fibrils. In particular, introduction of isotope labelled carbonyl into a peptide backbone, and incorporation of the extrinsic unnatural amino acids with vibrational moieties on the side chain, have greatly expanded the ability of vibrational spectroscopy to obtain site-specific structural and dynamic information. The applications of these methods in recent studies of protein aggregation are also reviewed.

scholarly journals Valorization of Apple Peels through the Study of the Effects on the Amyloid Aggregation Process of κ-Casein

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2371
Author(s):  
Valeria Guarrasi ◽  
Giacoma Cinzia Rappa ◽  
Maria Assunta Costa ◽  
Fabio Librizzi ◽  
Marco Raimondo ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Environmental Sustainability ◽  
Bovine Milk ◽  
Amyloid Formation ◽  
Aggregation Process ◽  
Amyloid Aggregation ◽  
Social Challenges ◽  
Force Microscopy ◽  
Atomic Force ◽  
Apple Peels

Waste valorization represents one of the main social challenges when promoting a circular economy and environmental sustainability. Here, we evaluated the effect of the polyphenols extracted from apple peels, normally disposed of as waste, on the amyloid aggregation process of κ-casein from bovine milk, a well-used amyloidogenic model system. The effect of the apple peel extract on protein aggregation was examined using a thioflavin T fluorescence assay, Congo red binding assay, circular dichroism, light scattering, and atomic force microscopy. We found that the phenolic extract from the peel of apples of the cultivar “Fuji”, cultivated in Sicily (Caltavuturo, Italy), inhibited κ-casein fibril formation in a dose-dependent way. In particular, we found that the extract significantly reduced the protein aggregation rate and inhibited the secondary structure reorganization that accompanies κ-casein amyloid formation. Protein-aggregated species resulting from the incubation of κ-casein in the presence of polyphenols under amyloid aggregation conditions were reduced in number and different in morphology.

scholarly journals The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Oscar Aubi ◽  
Karina S. Prestegård ◽  
Kunwar Jung-KC ◽  
Tie-Jun Sten Shi ◽  
Ming Ying ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Misfolding ◽  
Phenylalanine Hydroxylase ◽  
Hepatic Tissue ◽  
Loss Of Function ◽  
Advantageous Position ◽  
Protein Misfolding And Aggregation ◽  
Activity Decrease ◽  
Systemic Accumulation ◽  
Altered Lipid

AbstractPhenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.

scholarly journals Investigating the Disordered and Membrane-Active Peptide A-Cage-C Using Conformational Ensembles

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3607
Author(s):  
Olena Dobrovolska ◽  
Øyvind Strømland ◽  
Ørjan Sele Handegård ◽  
Martin Jakubec ◽  
Morten L. Govasli ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Protein Misfolding ◽  
Driving Forces ◽  
Conformational Space ◽  
Supported Bilayers ◽  
Conformational Ensembles ◽  
Protein Membrane ◽  
Chimeric Polypeptide ◽  
Protein Misfolding And Aggregation ◽  
In Silico Analyses

The driving forces and conformational pathways leading to amphitropic protein-membrane binding and in some cases also to protein misfolding and aggregation is the subject of intensive research. In this study, a chimeric polypeptide, A-Cage-C, derived from α-Lactalbumin is investigated with the aim of elucidating conformational changes promoting interaction with bilayers. From previous studies, it is known that A-Cage-C causes membrane leakages associated with the sporadic formation of amorphous aggregates on solid-supported bilayers. Here we express and purify double-labelled A-Cage-C and prepare partially deuterated bicelles as a membrane mimicking system. We investigate A-Cage-C in the presence and absence of these bicelles at non-binding (pH 7.0) and binding (pH 4.5) conditions. Using in silico analyses, NMR, conformational clustering, and Molecular Dynamics, we provide tentative insights into the conformations of bound and unbound A-Cage-C. The conformation of each state is dynamic and samples a large amount of overlapping conformational space. We identify one of the clusters as likely representing the binding conformation and conclude tentatively that the unfolding around the central W23 segment and its reorientation may be necessary for full intercalation at binding conditions (pH 4.5). We also see evidence for an overall elongation of A-Cage-C in the presence of model bilayers.

scholarly journals The Non-Protein Amino Acid BMAA Is Misincorporated into Human Proteins in Place of l-Serine Causing Protein Misfolding and Aggregation

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e75376 ◽  
Author(s):  
Rachael Anne Dunlop ◽  
Paul Alan Cox ◽  
Sandra Anne Banack ◽  
Kenneth John Rodgers
Keyword(s):  
Amino Acid ◽  
Protein Misfolding ◽  
Protein Amino Acid ◽  
Human Proteins ◽  
Protein Misfolding And Aggregation

Glutamine repeats: structural hypotheses and neurodegeneration

2002 ◽  
Vol 30 (4) ◽  
pp. 548-551 ◽  
Author(s):  
L. Masino ◽  
A. Pastore
Keyword(s):  
Protein Misfolding ◽  
Trinucleotide Repeats ◽  
Intranuclear Inclusions ◽  
The Past ◽  
Cag Trinucleotide Repeats ◽  
Protein Misfolding And Aggregation ◽  
Polyglutamine Protein ◽  
Molecular Bases ◽  
Protein Models

A growing number of neurodegenerative diseases are caused by expansion of CAG trinucleotide repeats coding for polyglutamine. The presence of intranuclear inclusions in the affected neuronal cells has suggested a mechanism for pathogenesis based on protein misfolding and aggregation. Detailed understanding of these phenomena is therefore crucial in order to rationalize different phases of the diseases. In the past decade, a few studies have focused on the structural properties of polyglutamine and on the molecular bases of the aggregation process. Most of these studies have been performed on polyglutamine peptides and protein models. Only one report is currently available on the characterization of a full-length polyglutamine protein. The structural hypotheses resulting from these studies are reviewed here.

Protein Misfolding and Aggregation of Tau Protein in Alzheimer’s Disease

2020 ◽  
pp. 139-146
Author(s):  
Madhura Chandrashekar ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Protein Misfolding ◽  
Protein Misfolding And Aggregation
Sign in / Sign up

Export Citation Format

Share Document