scholarly journals The folding space of protein β2-microglobulin is modulated by a single disulfide bond

2021 ◽  
Author(s):  
Jules Morand ◽  
Ana Nunes ◽  
Patricia FN Faisca

Protein beta-2-microglobulin (β2m) is classically considered the causative agent of dialysis related amyloidosis (DRA), a conformational disorder that affects patients undergoing long-term hemodialysis. Together with the wild type form, the ΔN6 structural variant, and the D76N mutant, have been extensively used as model systems of β2m aggregation. In all of them, the native structure is stabilized by a disulfide bridge between the sulphur atoms of the cysteine residues 25 (at B strand) and 80 (at F strand), which has been considered fundamental in β2m fibrillogenesis. Here, we use extensive Discrete Molecular Dynamics simulations of a full atomistic structure-based model to explore the role of this disulfide bridge as a modulator of the folding space of β2m. In particular, by considering different models for the disulfide bridge, we explore the thermodynamics of the folding transition, and the formation of intermediate states that may have the potential to trigger the aggregation cascade. Our results show that the dissulfide bridge affects folding transition and folding thermodynamics of the considered model systems, although to different extents. In particular, when the interaction between the sulphur atoms is stabilized relative to the other intramolecular interactions, or even locked (i.e. permanently established), the WT form populates an intermediate state featuring a well preserved core, and two unstructured termini, which was previously detected only for the D76N mutant. The formation of this intermediate state may have important implications in our understanding of β2m fibrillogenesis.

2021 ◽  
Vol 8 ◽  
Author(s):  
George V. Papamokos ◽  
George Tziatzos ◽  
Dimitrios G. Papageorgiou ◽  
Spyros Georgatos ◽  
Efthimios Kaxiras ◽  
...  

Protein phosphorylation is a key regulatory mechanism in eukaryotic cells. In the intrinsically disordered histone tails, phosphorylation is often a part of combinatorial post-translational modifications and an integral part of the “histone code” that regulates gene expression. Here, we study the association between two histone H3 tail peptides modified to different degrees, using fully atomistic molecular dynamics simulations. Assuming that the initial conformations are either α-helical or fully extended, we compare the propensity of the two peptides to associate with one another when both are unmodified, one modified and the other unmodified, or both modified. The simulations lead to the identification of distinct inter- and intramolecular interactions in the peptide dimer, highlighting a prominent role of a fine-tuned phosphorylation rheostat in peptide association. Progressive phosphorylation appears to modulate peptide charge, inducing strong and specific intermolecular interactions between the monomers, which do not result in the formation of amorphous or ordered aggregates, as documented by experimental evidence derived from Circular Dichroism and NMR spectroscopy. However, upon complete saturation of positive charges by phosphate groups, this effect is reversed: intramolecular interactions prevail and dimerization of zero-charge peptides is markedly reduced. These findings underscore the role of phosphorylation thresholds in the dynamics of intrinsically disordered proteins. Phosphorylation rheostats might account for the divergent effects of histone modifications on the modulation of chromatin structure.


2004 ◽  
Vol 100 (5) ◽  
pp. 1235-1241 ◽  
Author(s):  
Max T. Baker ◽  
Marc S. Gregerson ◽  
Mohamed Naguib

Background During long-term intravenous infusions, sulfite in sulfite-containing propofol emulsions can cause the peroxidation of lipid and dimerization of propofol. This study evaluated the role of lipid in sulfite-dependent propofol dimerization by determining the effects of individual fatty acids in soybean oil emulsion and peroxidized lipids in a model system. Methods Individual fatty acids, stearic (18:0), oleic (18:1), linoleic (18:2), linolenic (18:3), and arachidonic (20:4), were added to sulfite-containing propofol emulsion and incubated for 90 min at 37 degrees C. Model systems containing soybean oil (100 microl), water (900 microl), propofol (10 mg/ml), and sulfite (0.25 mg/ml) composed of oils with different peroxide values were allowed to react for 60 min at room temperature. After the reactions, propofol dimer and propofol dimer quinone were analyzed by reversed-phase high-pressure liquid chromatography. Results Propofol did not dimerize when added to aqueous sulfite unless soybean oil was also included. The addition of the polyunsaturated fatty acids (linoleic, linolenic, arachidonic) to sulfite-containing propofol emulsion resulted in large increases of propofol dimerization compared with stearic or oleic acid. Using biphasic mixtures of soybean oil and aqueous sulfite, propofol dimerization increased with increasing peroxide content of the oil. In propofol emulsion, lipoxidase and ferrous iron in the absence of sulfite also caused the dimerization of propofol. Conclusions These results show that lipid can play a significant role in sulfite-dependent propofol dimerization. The relation of dimerization to polyunsaturated fatty acid and soybean oil peroxide content suggests that sulfite reacts with unsaturated lipid or peroxide-modified lipid to facilitate propofol dimerization.


2019 ◽  
Vol 63 (6) ◽  
pp. 707-715 ◽  
Author(s):  
Allegra Angeloni ◽  
Ozren Bogdanovic

Abstract DNA methylation involves the addition of a methyl group to the fifth carbon of the pyrimidine cytosine ring (5-methylcytosine, 5mC). 5mC is widespread in vertebrate genomes where it is predominantly found within CpG dinucleotides. In mammals, 5mC participates in long-term silencing processes such as X-chromosome inactivation, genomic imprinting, somatic silencing of germline genes, and silencing of repetitive DNA elements. The evidence for 5mC as a dynamic gene-regulatory mechanism is mostly limited to specific examples, and is far from being completely understood. Recent work from diverse model systems suggests that 5mC might not always act as a dominant repressive mechanism and that hypermethylated promoters and enhancers can be permissive to transcription in vivo and in vitro. In this review, we discuss the links between 5mC and enhancer activity, and evaluate the role of this biochemical mechanism in various biological contexts.


2003 ◽  
Vol 28 ◽  
pp. 155-177
Author(s):  
José S. Carrión ◽  
Juan Guerra

RESUMEN. Macroevolución en plantas vasculares. Se revisan los sistemas jerarquizados de evolución vegetal, desde una perspectiva paleoecológica y con énfasis en los controles del nivel superior para las plantas vasculares. Este nivel supone la existencia de breves episodios de intensa radiación, seguidos por largas fases de estabilización y declive taxonómico. El registro fósil sugiere que no han existido extinciones masivas entre las plantas terrestres, en el sentido en que ésta expresión se emplea para la evolución de animales, es decir, la existencia de fuertes pérdidas de biodiversidacl en períodos breves de tiempo geológico comparados con la vida media de las especies. Durante los episodios de estrés ambiental, las plantas han reaccionado haciendo valer sus capacidades de migración, recolonización, desplazamiento competitivo y, en suma, reorganizando la estructura ecológica o fitogeográfica. A un nivel taxonómico elevado, la mayoría de los grandes grupos exhiben un importante componente de supervivencia (fósiles vivientes). El único estrés al que no han podido escapar parece haber sido el de tipo abiótico y extrínseco que supone el incremento atmosférico del dióxido de carbono durante los eventos de superpluma asociados a las pulsaciones tectónicas. De entre estas, aquellas constatables para el Ordovícico Medio-Silúrico (460- 430 Ma), Devónico Medio-Carbonífero Inferior (375-350 Ma), Jurásico (150 Ma) y Cretácico Inferior (120-80 Ma), se correlacionan con fases de incremento rápido en la especiación y con la aparición de nuevos proyectos reproductores, a saber embriófitos, espermatófitos, gimnospermas actuales y angiospermas respectivamente. El artículo concluye considerando las opciones dialécticas de la radiación difusiva frente a la hipótesis adaptacionista, el papel de la preadaptación y la evolución de la complejidad.Palabras clave. Evolución, paleobottinica, paleoecología, plantas terrestres, extinciones masivas, preadaptación, pulsaciones tectónicas.ABSTRACT. Macroevolution in vascular plants. Here we review hierarchical, evolutionary model systems for vascular plants from a palaeoecological perspective, with emphasis in the controls for the highest tier.This involves the existence of rapid events of radiation, followed by enduring phases of stabilization and taxonomic declining. The fossil record fails to recognize mass extinctions among terrestrial plants, at least in the sense adopted for the evolution of animals, namely, short periods of geological time involving strong losses of biodiversity if compared with average lifetimes of the extinct species. During stages of environmental stress, the vascular plants have exploted their capabilities to migration, recolonization, and competitive displacement; shortly, reorganization of the ecological and fitogeographic structure. At high taxonomic levels, most groups exhibit persistence, inertia, and survival rather than extinction, demonstrably through the existence of a number of living fossils among the main clades. The only environmental factor to which plants could not escape was extrinsic abiotic stress in the form of increasing atmospheric CO, during superplumes associated to tectonics pulsations. In fact, those dated at the Mid-Ordovician u; Silurian (460- 430 Ma), Mid-Devonian to Lower Carboniferous (375-350 Ma), Jurassic (150 Ma), and Lower Cretaceous (120-80 Ma), correlate with phases of rapid speciation within the principal reproductive groups, namely embriophytes, seed plants, gymnosperms, and angiosperms respectively. We conclude discussing related issues of palaeoecological concern, such as diffusive versus adaptive hypotheses of radiation, the role of preadaptation in plant evolution, and the long-term patterns of complexity.-Key words. Evolution, palaeobotany, palaeoecology, land plants, mass extinctions, preadaptation, pulsation tectonics.


2013 ◽  
Author(s):  
Francesca Menegazzo ◽  
Melissa Rosa Rizzotto ◽  
Martina Bua ◽  
Luisa Pinello ◽  
Elisabetta Tono ◽  
...  

2014 ◽  
pp. 30-52 ◽  
Author(s):  
L. Grigoryev ◽  
E. Buryak ◽  
A. Golyashev

The Ukrainian socio-economic crisis has been developing for years and resulted in the open socio-political turmoil and armed conflict. The Ukrainian population didn’t meet objectives of the post-Soviet transformation, and people were disillusioned for years, losing trust in the state and the Future. The role of workers’ remittances in the Ukrainian economy is underestimated, since the personal consumption and stability depend strongly on them. Social inequality, oligarchic control of key national assets contributed to instability as well as regional disparity, aggravated by identity differences. Economic growth is slow due to a long-term underinvestment, and prospects of improvement are dependent on some difficult institutional reforms, macro stability, open external markets and the elites’ consensus. Recovering after socio-economic and political crisis will need not merely time, but also governance quality improvement, institutions reform, the investment climate revival - that can be attributed as the second transformation in Ukraine.


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