scholarly journals In Silico Modeling of the Influence of Environment on Amyloid Folding Using FOD-M Model

2021 ◽  
Vol 22 (19) ◽  
pp. 10587
Author(s):  
Irena Roterman ◽  
Katarzyna Stapor ◽  
Piotr Fabian ◽  
Leszek Konieczny
Keyword(s):  
Characteristic Property ◽  
Polar Solvent ◽  
Amyloid Formation ◽  
Hydrophobic Residues ◽  
Intrinsically Disordered ◽  
Polar Environment ◽  
In Silico Modeling ◽  
A Chain ◽  
The Given

The role of the environment in amyloid formation based on the fuzzy oil drop model (FOD) is discussed here. This model assumes that the hydrophobicity distribution within a globular protein is consistent with a 3D Gaussian (3DG) distribution. Such a distribution is interpreted as the idealized effect of the presence of a polar solvent—water. A chain with a sequence of amino acids (which are bipolar molecules) determined by evolution recreates a micelle-like structure with varying accuracy. The membrane, which is a specific environment with opposite characteristics to the polar aquatic environment, directs the hydrophobic residues towards the surface. The modification of the FOD model to the FOD-M form takes into account the specificity of the cell membrane. It consists in “inverting” the 3DG distribution (complementing the Gaussian distribution), which expresses the exposure of hydrophobic residues on the surface. It turns out that the influence of the environment for any protein (soluble or membrane-anchored) is the result of a consensus factor expressing the participation of the polar environment and the “inverted” environment. The ratio between the proportion of the aqueous and the “reversed” environment turns out to be a characteristic property of a given protein, including amyloid protein in particular. The structure of amyloid proteins has been characterized in the context of prion, intrinsically disordered, and other non-complexing proteins to cover a wider spectrum of molecules with the given characteristics based on the FOD-M model.

scholarly journals Role of a DEF/Y motif in histone H2A-H2B recognition and nucleosome editing

2020 ◽  
Vol 117 (7) ◽  
pp. 3543-3550 ◽  
Author(s):  
Yan Huang ◽  
Lu Sun ◽  
Leonidas Pierrakeas ◽  
Linchang Dai ◽  
Lu Pan ◽  
...  
Keyword(s):  
Dna Interaction ◽  
General Strategy ◽  
Histone H2a ◽  
Hydrophobic Residues ◽  
Intrinsically Disordered ◽  
Chromatin Regulators ◽  
A Subunit

The SWR complex edits the histone composition of nucleosomes at promoters to facilitate transcription by replacing the two nucleosomal H2A-H2B (A-B) dimers with H2A.Z-H2B (Z-B) dimers. Swc5, a subunit of SWR, binds to A-B dimers, but its role in the histone replacement reaction was unclear. In this study, we showed that Swc5 uses a tandem DEF/Y motif within an intrinsically disordered region to engage the A-B dimer. A 2.37-Å X-ray crystal structure of the histone binding domain of Swc5 in complex with an A-B dimer showed that consecutive acidic residues and flanking hydrophobic residues of Swc5 form a cap over the histones, excluding histone–DNA interaction. Mutations in Swc5 DEF/Y inhibited the nucleosome editing function of SWR in vitro. Swc5 DEF/Y interacts with histones in vivo, and the extent of this interaction is dependent on the remodeling ATPase of SWR, supporting a model in which Swc5 acts as a wedge to promote A-B dimer eviction. Given that DEF/Y motifs are found in other evolutionary unrelated chromatin regulators, this work provides the molecular basis for a general strategy used repeatedly during eukaryotic evolution to mobilize histones in various genomic functions.

The Lipid-Chaperon Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins

2020 ◽  
Author(s):  
Michele F. M. Sciacca ◽  
Fabio Lolicato ◽  
Carmelo Tempra ◽  
Federica Scollo ◽  
Bikash R. Sahoo ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Membrane Damage ◽  
Amyloid Β ◽  
Disordered Proteins ◽  
Amyloid Formation ◽  
Intrinsically Disordered ◽  
Molecular Events ◽  
Membrane Poration ◽  
Synuclein Proteins

<p>Increasing number of human diseases have been shown to be linked to aggregation and amyloid formation by intrinsically disordered proteins (IDPs). Amylin, amyloid-β, and α-synuclein are, indeed, involved in type-II diabetes, Alzheimer’s, and Parkinson’s, respectively. Despite the correlation of the toxicity of these proteins at early aggregation stages with membrane damage, the molecular events underlying the process is quite complex to understand. In this study, we demonstrate the crucial role of free lipids in the formation of lipid-protein complex, which enables an easy membrane insertion for amylin, amyloid-β, and α-synuclein. Experimental results from a variety of biophysical methods and molecular dynamics results reveal this common molecular pathway in membrane poration is shared by amyloidogenic (amylin, amyloid-β, and α-synuclein) and non-amyloidogenic (rat IAPP, β-synuclein) proteins. Based on these results, we propose a “lipid-chaperone” hypothesis as a unifying framework for protein-membrane poration.<b></b></p>

scholarly journals Experimental Evidence of Intrinsic Disorder and Amyloid Formation by the Henipavirus W Proteins

2022 ◽  
Vol 23 (2) ◽  
pp. 923
Author(s):  
Giulia Pesce ◽  
Frank Gondelaud ◽  
Denis Ptchelkine ◽  
Juliet F. Nilsson ◽  
Christophe Bignon ◽  
...  
Keyword(s):  
Phase Separation ◽  
Critical Role ◽  
Limited Proteolysis ◽  
Size Exclusion ◽  
Amyloid Formation ◽  
Type I ◽  
Human Pathogens ◽  
Intrinsically Disordered ◽  
P Gene

Henipaviruses are severe human pathogens within the Paramyxoviridae family. Beyond the P protein, the Henipavirus P gene also encodes the V and W proteins which share with P their N-terminal, intrinsically disordered domain (NTD) and possess a unique C-terminal domain. Henipavirus W proteins antagonize interferon (IFN) signaling through NTD-mediated binding to STAT1 and STAT4, and prevent type I IFN expression and production of chemokines. Structural and molecular information on Henipavirus W proteins is lacking. By combining various bioinformatic approaches, we herein show that the Henipaviruses W proteins are predicted to be prevalently disordered and yet to contain short order-prone segments. Using limited proteolysis, differential scanning fluorimetry, analytical size exclusion chromatography, far-UV circular dichroism and small-angle X-ray scattering, we experimentally confirmed their overall disordered nature. In addition, using Congo red and Thioflavin T binding assays and negative-staining transmission electron microscopy, we show that the W proteins phase separate to form amyloid-like fibrils. The present study provides an additional example, among the few reported so far, of a viral protein forming amyloid-like fibrils, therefore significantly contributing to enlarge our currently limited knowledge of viral amyloids. In light of the critical role of the Henipavirus W proteins in evading the host innate immune response and of the functional role of phase separation in biology, these studies provide a conceptual asset to further investigate the functional impact of the phase separation abilities of the W proteins.

scholarly journals The Lipid-Chaperon Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins

2020 ◽  
Author(s):  
Michele F. M. Sciacca ◽  
Fabio Lolicato ◽  
Carmelo Tempra ◽  
Federica Scollo ◽  
Bikash R. Sahoo ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Membrane Damage ◽  
Amyloid Β ◽  
Disordered Proteins ◽  
Amyloid Formation ◽  
Intrinsically Disordered ◽  
Molecular Events ◽  
Membrane Poration ◽  
Synuclein Proteins

<p>Increasing number of human diseases have been shown to be linked to aggregation and amyloid formation by intrinsically disordered proteins (IDPs). Amylin, amyloid-β, and α-synuclein are, indeed, involved in type-II diabetes, Alzheimer’s, and Parkinson’s, respectively. Despite the correlation of the toxicity of these proteins at early aggregation stages with membrane damage, the molecular events underlying the process is quite complex to understand. In this study, we demonstrate the crucial role of free lipids in the formation of lipid-protein complex, which enables an easy membrane insertion for amylin, amyloid-β, and α-synuclein. Experimental results from a variety of biophysical methods and molecular dynamics results reveal this common molecular pathway in membrane poration is shared by amyloidogenic (amylin, amyloid-β, and α-synuclein) and non-amyloidogenic (rat IAPP, β-synuclein) proteins. Based on these results, we propose a “lipid-chaperone” hypothesis as a unifying framework for protein-membrane poration.<b></b></p>

THE ISSUE OF MINORS’S GUARDIANSHIP SENTENCED TO IMPRISONMENT

2020 ◽  
pp. 33-37
Author(s):  
Ирина Викторовна Евстафьева
Keyword(s):  
Juvenile Offenders ◽  
Legal Status ◽  
Careful Consideration ◽  
Point Of View ◽  
Sufficient Detail ◽  
Domestic Legislation ◽  
The Status ◽  
Correct Understanding ◽  
The Given

В статье исследуются вопросы попечительства в отношении несовершеннолетних, отбывающих наказание в виде лишения свободы. Проблема, поднимаемая автором настоящей статьи, многогранна, касается различных аспектов отбывания наказания несовершеннолетними в воспитательных колониях и требует комплексного исследования, способного ответить на определенно значимый вопрос: является ли колония законным представителем находящихся в ней несовершеннолетних со всеми вытекающими из статуса законных представителей последствиями. При этом необходимо обращать внимание на специфику правового статуса лиц, отбывающих наказание в воспитательных колониях, которые, во-первых, являются несовершеннолетними, то есть не обладают дееспособностью в полном объеме и нуждаются в особой заботе, защите и представительстве, а во-вторых, осуждены за совершение тяжкого или особо тяжкого преступления, влекущего изоляцию от общества и определенные ограничения и лишения. Отечественное законодательство достаточно детально регламентирует особенности режима отбывания наказания в виде лишения свободы несовершеннолетними, не определяя при этом статуса воспитательных колоний, кем они являются: воспитателями, попечителями или исключительно учреждениями исполнения наказаний. Между тем правильное понимание значения и роли воспитательной колонии в жизни находящихся в ней несовершеннолетних преступников, по мнению автора, поможет избежать ряда проблем, объективно складывающихся в учреждениях подобного рода. С этой точки зрения предлагаемая тема представляет интерес не только для ученых-теоретиков, но и для практиков - сотрудников соответствующих учреждений. Особо следует подчеркнуть, что исследований по данной тематике в специальной литературе нет. Отдельные исследования, встречающиеся в современной литературе, касаются исключительно общего гражданско-правового статуса несовершеннолетних осужденных. Однако это обстоятельство может свидетельствовать только о новизне данной темы, но никак не об отсутствии самой проблемы. The article analyzes the issues of the status of educational colonies as guardians of minors serving a sentence of imprisonment. In fact, the problem raised by the author of this article is multifaceted, concerns various aspects of the serving of punishment by minors in educational colonies and requires a comprehensive study that can answer, it seems, a definitely significant question: whether the colony is the legal representative of the minors in it with all the consequences arising from the status of legal representatives in the form of duties and responsibilities. At the same time, it seems, it is necessary to pay attention to the specifics of the legal status of citizens serving sentences in educational colonies, who, firstly, are minors, i.e. do not have full legal capacity and need special care, protection and representation, and, secondly, are convicted of committing a serious or particularly serious crime, entailing isolation from society and certain restrictions and deprivation. Domestic legislation regulates in sufficient detail the peculiarities of the regime of serving sentences in the form of deprivation of liberty by minors, without determining the status of educational colonies. Who are they: educators, Trustees or only institutions of execution of punishments. Meanwhile, the correct understanding of the importance and role of the educational colony in the life of juvenile offenders in it, according to the author, will help to avoid a number of problems that objectively develop in institutions of this kind. From this point of view, the proposed topic is of interest not only for theoretical scientists, but for practitioners-employees of relevant institutions. It should be emphasized that there are no studies on this subject in the special literature. However, this circumstance can testify only about novelty of the given subject, but in any way about absence of the problem. It seems that the relevance and importance of a problem is not always measured by the number of studies devoted to it. Sometimes these its traits are manifest only under particularly careful consideration.

scholarly journals Ostracism and nationalism in the workplace: discursive exclusionary practices between cultural and geographic neighbors

2021 ◽  
Author(s):  
Thomas Köllen ◽  
Susanne Kopf
Keyword(s):  
Turnover Intention ◽  
National Identities ◽  
Exclusionary Practices ◽  
Online Comments ◽  
Norm Group ◽  
Employee Groups ◽  
The Given ◽  
Organizational Mechanisms ◽  
Shed Light

AbstractSo far, management research on mechanisms of exclusion of employee groups has mainly applied constructs of racism to understanding issues of origin-based ostracism. This research has primarily focused on issues faced by employees whose heritage is markedly different from the heritage shared by the norm group in the given socio-cultural, linguistic, and geographical setting. Against this backdrop, the present study investigates how ostracism plays out when the heritages involved are similar, as exemplified by German employees in Austria. Study 1 examines the discursive production of Austrian stereotyping of Germans in the usage of different terms of reference for ‘Germans’ in Austrian discourse. A corpus analysis of online comments on newspaper sites highlights the implicit Austrian need for delineation against Germany. Study 2 analyzes Germans’ perception of Austrians’ exclusionary linguistic practices and how this impacts on their employment experience and turnover intention. A quantitative analysis of survey data from 600 German nationals employed in Austria reveals that the degree of exposure to these demarcating practices is associated with lower job satisfaction, a higher burnout level and an increase in turnover intention. This study is amongst the first to shed light on the central role of nationalism and national identities in organizational mechanisms of exclusion.

scholarly journals Backbone assignments, and effect of Asn deamidation, of the N-terminal region of the partitioning protein IncC1 from the plasmid RK2

2021 ◽  
Author(s):  
M. Fayyaz Rehman ◽  
M. Jeeves ◽  
E. I. Hyde
Keyword(s):  
Amino Acids ◽  
Chemical Shift Assignments ◽  
Backbone Assignments ◽  
Intrinsically Disordered ◽  
Nmr Chemical Shift Assignments ◽  
Protein Partner ◽  
Copy Number Plasmid ◽  
Low Copy Number ◽  
Plasmid Rk2

AbstractIncC from the low-copy number plasmid RK2, is a member of the ParA family of proteins required for partitioning DNA in many bacteria and plasmids. It is an ATPase that binds DNA and its ParB protein partner, KorB. Together, the proteins move replicated DNA to appropriate cellular positions, so that each daughter cell inherits a copy on cell division. IncC from RK2 is expressed in two forms. IncC2 is homologous to bacterial ParA proteins, while IncC1 has an N-terminal extension of 105 amino acids and is similar in length to ParA homologues in other plasmids. We have been examining the role of this extension, here called IncC NTD. We present its backbone NMR chemical shift assignments and show that it is entirely intrinsically disordered. The assignments were achieved using C-detected, CON-based spectra, complemented by HNN spectra to obtain connectivities from three adjacent amino acids. We also observed evidence of deamidation of the protein at a GNGG sequence, to give isoAsp, giving 2 sets of peaks for residues up to 5 amino acids on either side of the modification. We have assigned resonances from around the position of modification for this form of the protein.

scholarly journals Connecting the αα-hubs: same fold, disordered ligands, new functions

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lasse Staby ◽  
Katrine Bugge ◽  
Rasmus Greve Falbe-Hansen ◽  
Edoardo Salladini ◽  
Karen Skriver ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Telomere Elongation ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Functional Understanding ◽  
Signal Specificity ◽  
Telomere Regulation ◽  
Secondary Structure Motif

Abstract Background Signal fidelity depends on protein–protein interaction–‘hubs’ integrating cues from large interactomes. Recently, and based on a common secondary structure motif, the αα-hubs were defined, which are small α-helical domains of large, modular proteins binding intrinsically disordered transcriptional regulators. Methods Comparative structural biology. Results We assign the harmonin-homology-domain (HHD, also named the harmonin N-terminal domain, NTD) present in large proteins such as harmonin, whirlin, cerebral cavernous malformation 2, and regulator of telomere elongation 1 to the αα-hubs. The new member of the αα-hubs expands functionality to include scaffolding of supra-modular complexes mediating sensory perception, neurovascular integrity and telomere regulation, and reveal novel features of the αα-hubs. As a common trait, the αα-hubs bind intrinsically disordered ligands of similar properties integrating similar cellular cues, but without cross-talk. Conclusion The inclusion of the HHD in the αα-hubs has uncovered new features, exemplifying the utility of identifying groups of hub domains, whereby discoveries in one member may cross-fertilize discoveries in others. These features make the αα-hubs unique models for decomposing signal specificity and fidelity. Using these as models, together with other suitable hub domain, we may advance the functional understanding of hub proteins and their role in cellular communication and signaling, as well as the role of intrinsically disordered proteins in signaling networks.

scholarly journals Compositional Determinants of Prion Formation in Yeast

2009 ◽  
Vol 30 (1) ◽  
pp. 319-332 ◽  
Author(s):  
James A. Toombs ◽  
Blake R. McCarty ◽  
Eric D. Ross
Keyword(s):  
Amino Acid ◽  
Amino Acid Composition ◽  
Amyloid Formation ◽  
Yeast Prion ◽  
Hydrophobic Residues ◽  
Predictive Methods ◽  
Infectious Proteins ◽  
Β Sheet ◽  
Eukaryotic Genomes

ABSTRACT Numerous prions (infectious proteins) have been identified in yeast that result from the conversion of soluble proteins into β-sheet-rich amyloid-like protein aggregates. Yeast prion formation is driven primarily by amino acid composition. However, yeast prion domains are generally lacking in the bulky hydrophobic residues most strongly associated with amyloid formation and are instead enriched in glutamines and asparagines. Glutamine/asparagine-rich domains are thought to be involved in both disease-related and beneficial amyloid formation. These domains are overrepresented in eukaryotic genomes, but predictive methods have not yet been developed to efficiently distinguish between prion and nonprion glutamine/asparagine-rich domains. We have developed a novel in vivo assay to quantitatively assess how composition affects prion formation. Using our results, we have defined the compositional features that promote prion formation, allowing us to accurately distinguish between glutamine/asparagine-rich domains that can form prion-like aggregates and those that cannot. Additionally, our results explain why traditional amyloid prediction algorithms fail to accurately predict amyloid formation by the glutamine/asparagine-rich yeast prion domains.

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