Publications by authors named "Vladimir N Uversky"

751 Publications

Structural Protein Analysis of Driver Gene Mutations in Conjunctival Melanoma.

Genes (Basel) 2021 Oct 15;12(10). Epub 2021 Oct 15.

Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

In recent years, there has been tremendous enthusiasm with respect to detailing the genetic basis of many neoplasms, including conjunctival melanoma (CM). We aim to analyze five proteins associated with CM, namely BRAF, NRAS, c-KIT, NF1, and PTEN. We evaluated each protein for its intrinsically disordered protein regions (IDPRs) and its protein-protein interactions (PPI) with the Predictor of Natural Disordered Protein Regions (PONDR) and the Search Tool for the Retrieval of Interacting Genes (STRING). Our PONDR analysis found high levels of IDPRs in all five proteins with mutations linked to CM. The highest levels of IDPRs were in BRAF (45.95%), followed by PTEN (31.76%), NF1 (22.19%), c-KIT (21.82%), and NRAS (14.81%). Our STRING analysis found that each of these five proteins had more predicted interactions then expected (-value < 1.0 × 10). Our analysis demonstrates that the mutations linked to CM likely affected IDPRs and possibly altered their highly complex PPIs. Quantifying IDPRs in BRAF, NRAS, c-KIT, NF1, and PTEN and understanding these protein regions are important processes as IDPRs can be possible drug targets for novel targeted therapies for treating CM.
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http://dx.doi.org/10.3390/genes12101625DOI Listing
October 2021

Preface: The Patchwork Quilt of Intrinsic Disorder.

Prog Mol Biol Transl Sci 2021 ;183:xiii-xviii

Department of Molecular Medicine and Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States.

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http://dx.doi.org/10.1016/S1877-1173(21)00182-4DOI Listing
January 2021

Non-specific porins of Gram-negative bacteria as proteins containing intrinsically disordered regions with amyloidogenic potential.

Prog Mol Biol Transl Sci 2021 14;183:75-99. Epub 2021 Jul 14.

G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far East Branch, Russian Academy of Sciences, Vladivostok, Russia.

Features of the structure and functional activity of bacterial outer membrane porins, coupled with their dynamic "behavior," suggests that intrinsically disordered regions (IDPRs) are contained in their structure. Using bioinformatic analysis, the quantitative content of amyloidogenic regions in the amino acid sequence of non-specific porins inhabiting various natural niches was determined: from terrestrial bacteria of the genus Yersinia (OmpF and OmpC proteins of Y. pseudotuberculosis and Y. ruckeri) and from the marine bacterium Marinomonas primoryensis (MpOmp). It was found that OmpF and OmpC porins can be classified as moderately disordered proteins, while MpOmp can be classified as highly disordered protein. Mapping of IDPRs, performed using 3D structures of monomers of the proteins, showed that the regions of increased conformational plasticity fall on the regions, the functional importance of which has been reliably confirmed as a result of numerous experimental studies. The revealed correlation made it possible to explain the differences in the physicochemical characteristics and properties of not only porins from terrestrial and marine bacteria, but also non-specific porins of different types, OmpF and OmpC proteins. First of all, this concerns the flexible outer loops that form the pore vestibule, as well as regions of the barrel with an increased "ability" for aggregation, the so-called "hot spots" of aggregation. The abnormally high content of IDPRs in the MpOmp structure made it possible to suggest that the high adaptive potential of bacteria may correlate with an increase in the number of IDPRs and/or regions with increased conformational variability.
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http://dx.doi.org/10.1016/bs.pmbts.2021.06.012DOI Listing
July 2021

Intrinsically disordered proteins: Chronology of a discovery.

Biophys Chem 2021 Sep 29;279:106694. Epub 2021 Sep 29.

Department of Medical Oncology, City of Hope National Medical Center, 1500 Duarte Rd, Duarte, CA, United States.

Intrinsic disorder is a new reality that appears to penetrate every corner of modern protein science. It is difficult to imagine that only 20 years ago the situation was completely different, and almost nobody had heard about 'structure-less' but functional proteins. As a matter of fact, for many at that time, this idea was completely heretical when viewed in light of the then dominating lock-and-key model describing the protein structure-function relationship, where a unique amino acid sequence defines a unique crystal-like 3D structure that serves as a prerequisite for a unique function of a protein. It seems like the entire field of protein intrinsic disorder has magically emerged at the turn of the century due to a revelation to a small group of researchers. Although this may very well be true, literature shows that the first observations contradicting the lock-and-key view of protein functionality started to appear almost immediately after this model was proposed. The goal of this article is to provide a brief chronology (though admittedly a subjective one) of the events in the field of protein science that eventually culminated in the discovery of the protein intrinsic disorder phenomenon. The entire process represents a good example of the "dwarf standing on the shoulders of giants" (Latin: nanos gigantum humeris insidentes) metaphor, where the truth is discovered by building on previous discoveries.
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http://dx.doi.org/10.1016/j.bpc.2021.106694DOI Listing
September 2021

Evolutionary Signatures Governing the Codon Usage Bias in Coronaviruses and Their Implications for Viruses Infecting Various Bat Species.

Viruses 2021 09 16;13(9). Epub 2021 Sep 16.

Zoonotic Diseases Group, ICAR-National Institute of High Security Animal Diseases, Bhopal 462022, India.

Many viruses that cause serious diseases in humans and animals, including the betacoronaviruses (beta-CoVs), such as SARS-CoV, MERS-CoV, and the recently identified SARS-CoV-2, have natural reservoirs in bats. Because these viruses rely entirely on the host cellular machinery for survival, their evolution is likely to be guided by the link between the codon usage of the virus and that of its host. As a result, specific cellular microenvironments of the diverse hosts and/or host tissues imprint peculiar molecular signatures in virus genomes. Our study is aimed at deciphering some of these signatures. Using a variety of genetic methods we demonstrated that trends in codon usage across chiroptera-hosted CoVs are collaboratively driven by geographically different host-species and temporal-spatial distribution. We not only found that chiroptera-hosted CoVs are the ancestors of SARS-CoV-2, but we also revealed that SARS-CoV-2 has the codon usage characteristics similar to those seen in CoVs infecting the sp. Surprisingly, the envelope gene of beta-CoVs infecting sp., including SARS-CoV-2, had extremely high CpG levels, which appears to be an evolutionarily conserved trait. The dissection of the furin cleavage site of various CoVs infecting hosts revealed host-specific preferences for arginine codons; however, arginine is encoded by a wider variety of synonymous codons in the murine CoV (MHV-A59) furin cleavage site. Our findings also highlight the latent diversity of CoVs in mammals that has yet to be fully explored.
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http://dx.doi.org/10.3390/v13091847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473330PMC
September 2021

Implications derived from S-protein variants of SARS-CoV-2 from six continents.

Int J Biol Macromol 2021 Sep 24;191:934-955. Epub 2021 Sep 24.

Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Institutskiy pereulok, 9, Dolgoprudny, 141700, Russia. Electronic address:

The spike (S) protein is a critical determinant of the infectivity and antigenicity of SARS-CoV-2. Several mutations in the S protein of SARS-CoV-2 have already been detected, and their effect in immune system evasion and enhanced transmission as a cause of increased morbidity and mortality are being investigated. From pathogenic and epidemiological perspectives, S proteins are of prime interest to researchers. This study focused on the unique variants of S proteins from six continents: Asia, Africa, Europe, Oceania, South America, and North America. In comparison to the other five continents, Africa had the highest percentage of unique S proteins (29.1%). The phylogenetic relationship implies that unique S proteins from North America are significantly different from those of the other five continents. They are most likely to spread to the other geographic locations through international travel or naturally by emerging mutations. It is suggested that restriction of international travel should be considered, and massive vaccination as an utmost measure to combat the spread of the COVID-19 pandemic. It is also further suggested that the efficacy of existing vaccines and future vaccine development must be reviewed with careful scrutiny, and if needed, further re-engineered based on requirements dictated by new emerging S protein variants.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.09.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462006PMC
September 2021

Periodically aperiodic pattern of SARS-CoV-2 mutations underpins the uncertainty of its origin and evolution.

Environ Res 2021 Sep 22:112092. Epub 2021 Sep 22.

Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA; Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Institutskiy pereulok, 9, Dolgoprudny, 141700, Russia. Electronic address:

Various lineages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have contributed to prolongation of the coronavirus disease 2019 (COVID-19) pandemic. Several non-synonymous mutations in SARS-CoV-2 proteins have generated multiple SARS-CoV-2 variants. In our previous report, we have shown an evenly uneven distribution of unique protein variants of SARS-CoV-2 is geo-location or demography-specific. However, the correlation between the demographic transmutability of the SARS-CoV-2 infection and mutations in various proteins remains unknown due to hidden symmetry/asymmetry in the occurrence of mutations. This study tracked how these mutations are emerging in SARS-CoV-2 proteins in six model countries and globally. In a geo-location, considering the mutations having a frequency of detection of at least five hundred in each SARS-CoV-2 protein; we studied the country-wise percentage of invariant residues. Our data revealed that since October 2020, highly frequent mutations in SARS-CoV-2 have been observed mostly in the Open Reading Frames (ORF) 7b and ORF8, worldwide. No such highly frequent mutations in any of the SARS-CoV-2 proteins were found in the UK, India, and Brazil, which does not correlate with the degree of transmissibility of the virus in India and Brazil. However, we have found a signature that SARS-CoV-2 proteins were evolving at a higher rate, and considering global data, mutations are detected in the majority of the available amino acid locations. Fractal analysis of each protein's normalized factor time series showed a periodically aperiodic emergence of dominant variants for SARS-CoV-2 protein mutations across different countries. It was noticed that certain high-frequency variants have emerged in the last couple of months, and thus the emerging SARS-CoV-2 strains are expected to contain prevalent mutations in ORF3a, membrane, and ORF8 proteins. In contrast to other beta-coronaviruses, SARS-CoV-2 variants have rapidly emerged based on demographically dependent mutations. Characterization of the periodically aperiodic nature of the demographic spread of SARS-CoV-2 variants in various countries can contribute to the identification of the origin of SARS-CoV-2.
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http://dx.doi.org/10.1016/j.envres.2021.112092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457672PMC
September 2021

Challenges and limitations in the studies of glycoproteins: A computational chemist's perspective.

Proteins 2021 Sep 22. Epub 2021 Sep 22.

Molecular Biotechnology, Turkish-German University, Istanbul, Turkey.

Experimenters face challenges and limitations while analyzing glycoproteins due to their high flexibility, stereochemistry, anisotropic effects, and hydration phenomena. Computational studies complement experiments and have been used in characterization of the structural properties of glycoproteins. However, recent investigations revealed that computational studies face significant challenges as well. Here, we introduce and discuss some of these challenges and weaknesses in the investigations of glycoproteins. We also present requirements of future developments in computational biochemistry and computational biology areas that could be necessary for providing more accurate structural property analyses of glycoproteins using computational tools. Further theoretical strategies that need to be and can be developed are discussed herein.
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http://dx.doi.org/10.1002/prot.26242DOI Listing
September 2021

Autoimmunity roots of the thrombotic events after COVID-19 vaccination.

Autoimmun Rev 2021 Nov 9;20(11):102941. Epub 2021 Sep 9.

Department of Molecular Medicine, University of South Florida, Tampa, FL, United States. Electronic address:

Although vaccination represents the most promising way to stop or contain the coronavirus disease 2019 (COVID-19) pandemic and safety and effectiveness of available vaccines were proven, a small number of individuals who received anti-SARS-CoV-2 vaccines developed a prothrombotic syndrome. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can be triggered by the adenoviral vector-based vaccine, whereas lipid nanoparticle-mRNA-based vaccines can induce rare cases of deep vein thrombosis (DVT). Although the main pathogenic mechanisms behind this rare phenomenon have not yet been identified, both host and vaccine factors might be involved, with pathology at least in part being related to the vaccine-triggered autoimmune reaction. In this review, we are considering some aspects related to pathogenesis, major risk factors, as well as peculiarities of diagnosis and treatment of this rare condition.
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http://dx.doi.org/10.1016/j.autrev.2021.102941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426137PMC
November 2021

Intrinsic Disorder in Human RNA-Binding Proteins.

J Mol Biol 2021 Oct 3;433(21):167229. Epub 2021 Sep 3.

Department of Computer Science, Virginia Commonwealth University, Richmond, VA 23284, USA. Electronic address:

Although RNA-binding proteins (RBPs) are known to be enriched in intrinsic disorder, no previous analysis focused on RBPs interacting with specific RNA types. We fill this gap with a comprehensive analysis of the putative disorder in RBPs binding to six common RNA types: messenger RNA (mRNA), transfer RNA (tRNA), small nuclear RNA (snRNA), non-coding RNA (ncRNA), ribosomal RNA (rRNA), and internal ribosome RNA (irRNA). We also analyze the amount of putative intrinsic disorder in the RNA-binding domains (RBDs) and non-RNA-binding-domain regions (non-RBD regions). Consistent with previous studies, we show that in comparison with human proteome, RBPs are significantly enriched in disorder. However, closer examination finds significant enrichment in predicted disorder for the mRNA-, rRNA- and snRNA-binding proteins, while the proteins that interact with ncRNA and irRNA are not enriched in disorder, and the tRNA-binding proteins are significantly depleted in disorder. We show a consistent pattern of significant disorder enrichment in the non-RBD regions coupled with low levels of disorder in RBDs, which suggests that disorder is relatively rarely utilized in the RNA-binding regions. Our analysis of the non-RBD regions suggests that disorder harbors posttranslational modification sites and is involved in the putative interactions with DNA. Importantly, we utilize experimental data from DisProt and independent data from Pfam to validate the above observations that rely on the disorder predictions. This study provides new insights into the distribution of disorder across proteins that bind different RNA types and the functional role of disorder in the regions where it is enriched.
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http://dx.doi.org/10.1016/j.jmb.2021.167229DOI Listing
October 2021

The role of amyloids in Alzheimer's and Parkinson's diseases.

Int J Biol Macromol 2021 Nov 2;190:44-55. Epub 2021 Sep 2.

Interdisciplinary Biotechnology Unit, A. M. U., Aligarh 202002, India.

With varying clinical symptoms, most neurodegenerative diseases are associated with abnormal loss of neurons. They share the same common pathogenic mechanisms involving misfolding and aggregation, and these visible aggregates of proteins are deposited in the central nervous system. Amyloid formation is thought to arise from partial unfolding of misfolded proteins leading to the exposure of hydrophobic surfaces, which interact with other similar structures and give rise to form dimers, oligomers, protofibrils, and eventually mature fibril aggregates. Accumulating evidence indicates that amyloid oligomers, not amyloid fibrils, are the most toxic species that causes Alzheimer's disease (AD) and Parkinson's disease (PD). AD has recently been recognized as the 'twenty-first century plague', with an incident rate of 1% at 60 years of age, which then doubles every fifth year. Currently, 5.3 million people in the US are afflicted with this disease, and the number of cases is expected to rise to 13.5 million by 2050. PD, a disorder of the brain, is the second most common form of dementia, characterized by difficulty in walking and movement. Keeping the above views in mind, in this review we have focused on the roles of amyloid in neurodegenerative diseases including AD and PD, the involvement of amyloid in mitochondrial dysfunction leading to neurodegeneration, are also considered in the review.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.08.197DOI Listing
November 2021

On the roles of intrinsically disordered proteins and regions in cell communication and signaling.

Cell Commun Signal 2021 Aug 30;19(1):88. Epub 2021 Aug 30.

Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.

For proteins, the sequence → structure → function paradigm applies primarily to enzymes, transmembrane proteins, and signaling domains. This paradigm is not universal, but rather, in addition to structured proteins, intrinsically disordered proteins and regions (IDPs and IDRs) also carry out crucial biological functions. For these proteins, the sequence → IDP/IDR ensemble → function paradigm applies primarily to signaling and regulatory proteins and regions. Often, in order to carry out function, IDPs or IDRs cooperatively interact, either intra- or inter-molecularly, with structured proteins or other IDPs or intermolecularly with nucleic acids. In this IDP/IDR thematic collection published in Cell Communication and Signaling, thirteen articles are presented that describe IDP/IDR signaling molecules from a variety of organisms from humans to fruit flies and tardigrades ("water bears") and that describe how these proteins and regions contribute to the function and regulation of cell signaling. Collectively, these papers exhibit the diverse roles of disorder in responding to a wide range of signals as to orchestrate an array of organismal processes. They also show that disorder contributes to signaling in a broad spectrum of species, ranging from micro-organisms to plants and animals.
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http://dx.doi.org/10.1186/s12964-021-00774-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404256PMC
August 2021

S-layer protein 2 of vaginal Lactobacillus crispatus 2029 enhances growth, differentiation, VEGF production and barrier functions in intestinal epithelial cell line Caco-2.

Int J Biol Macromol 2021 Oct 24;189:410-419. Epub 2021 Aug 24.

Department of Science, Engineering and Computing, Kingston University London, Kingston upon Thames KT1 2EE, UK.

We have previously demonstrated the ability of the human vaginal strain Lactobacillus crispatus 2029 (LC2029) for strong adhesion to cervicovaginal epithelial cells, expression of the surface layer protein 2 (Slp2), and antagonistic activity against urogenital pathogens. Slp2 forms regular two-dimensional structure around the LC2029 cells,which is secreted into the medium and inhibits intestinal pathogen-induced activation of caspase-9 and caspase-3 in the human intestinal Caco-2 cells. Here, we elucidated the effects of soluble Slp2 on adhesion of proteobacteria pathogens inducing necrotizing enterocolitis (NEC), such as Escherichia coli ATCC E 2348/69, E. coli ATCC 31705, Salmonella Enteritidis ATCC 13076, Campylobacter jejuni ATCC 29428, and Pseudomonas aeruginosa ATCC 27853 to Caco-2 cells, as well as on growth promotion, differentiation, vascular endothelial growth factor (VEGF) production, and intestinal barrier function of Caco-2 cell monolayers. Slp2 acts as anti-adhesion agent for NEC-inducing proteobacteria, promotes growth of immature Caco-2 cells and their differentiation, and enhances expression and functional activity of sucrase, lactase, and alkaline phosphatase. Slp2 stimulates VEGF production, decreases paracellular permeability, and increases transepithelial electrical resistance, strengthening barrier function of Caco-2 cell monolayers. These data support the important role of Slp2 in the early postnatal development of the human small intestine enterocytes.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.08.150DOI Listing
October 2021

Interface-based design of the favipiravir-binding site in SARS-CoV-2 RNA-dependent RNA polymerase reveals mutations conferring resistance to chain termination.

FEBS Lett 2021 09 1;595(18):2366-2382. Epub 2021 Sep 1.

Molecular and Structural Biophysics Laboratory, Department of Biochemistry, North-Eastern Hill University, Shillong, India.

Favipiravir is a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp) currently being used to manage COVID-19. Accumulation of mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRp may facilitate antigenic drift, generating favipiravir resistance. Focussing on the chain-termination mechanism utilized by favipiravir, we used high-throughput interface-based protein design to generate > 100 000 designs of the favipiravir-binding site of RdRp and identify mutational hotspots. We identified several single-point mutants and designs having a sequence identity of 97%-98% with wild-type RdRp, suggesting that SARS-CoV-2 can develop favipiravir resistance with few mutations. Out of 134 mutations documented in the CoV-GLUE database, 63 specific mutations were already predicted as resistant in our calculations, thus attaining ˜ 47% correlation with the sequencing data. These findings improve our understanding of the potential signatures of adaptation in SARS-CoV-2 against favipiravir.
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http://dx.doi.org/10.1002/1873-3468.14182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426738PMC
September 2021

A Bird's-Eye View of Proteomics.

Curr Protein Pept Sci 2021 Aug 12. Epub 2021 Aug 12.

Biological Sciences Department, Faculty of Science, and Laboratory Department, University Medical Services Center, King Abdulaziz University, Jeddah. Saudi Arabia.

Modern protein science is broadening horizons by moving toward the systemic description of proteins in their natural habitats. This implies a transition from a classical reductionist approach associated with consideration of the unique structure and specific biological activity of an individual protein in a purified form to studying entire proteomes and their functions. This mini-review provides a brief description of structural, functional, and expression proteomics, the dark proteome (or unfoldome), and some of the tools utilized in the analyses of proteomes.
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http://dx.doi.org/10.2174/1389203722666210812120751DOI Listing
August 2021

Per aspera ad chaos: a personal journey to the wonderland of intrinsic disorder.

Biochem J 2021 Aug;478(15):3015-3024

Department of Molecular Medicine and Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, U.S.A.

This perspective article describes some of the key points of my personal journey through the intriguing world of intrinsically disordered proteins (IDPs). It also shows the evolution of my perception of functional proteins from a standard lock-and-key theory, where a unique function is defined by a unique 3D structure, to the structure-function continuum model, where the structural heterogeneity and conformational plasticity of IDPs define their remarkable multifunctionality and binding promiscuity. These personal accounts of the difficult and lengthy transition from order to disorder paralleled the uneasy and challenging transition in the mind of the scientific community from disbelief in intrinsic disorder to acceptance of IDPs as real entities that play critical biological roles. I hope that this perspective will be of interest to the readers of this journal.
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http://dx.doi.org/10.1042/BCJ20210146DOI Listing
August 2021

COVID-19 Vaccines and Thrombosis-Roadblock or Dead-End Street?

Biomolecules 2021 07 13;11(7). Epub 2021 Jul 13.

Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.

Two adenovirus-based vaccines, ChAdOx1 nCoV-19 and Ad26.COV2.S, and two mRNA-based vaccines, BNT162b2 and mRNA.1273, have been approved by the European Medicines Agency (EMA), and are invaluable in preventing and reducing the incidence of coronavirus disease-2019 (COVID-19). Recent reports have pointed to thrombosis with associated thrombocytopenia as an adverse effect occurring at a low frequency in some individuals after vaccination. The causes of such events may be related to SARS-CoV-2 spike protein interactions with different C-type lectin receptors, heparan sulfate proteoglycans (HSPGs) and the CD147 receptor, or to different soluble splice variants of the spike protein, adenovirus vector interactions with the CD46 receptor or platelet factor 4 antibodies. Similar findings have been reported for several viral diseases after vaccine administration. In addition, immunological mechanisms elicited by viral vectors related to cellular delivery could play a relevant role in individuals with certain genetic backgrounds. Although rare, the potential COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) requires immediate validation, especially in risk groups, such as the elderly, chronic smokers, and individuals with pre-existing incidences of thrombocytopenia; and if necessary, a reformulation of existing vaccines.
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http://dx.doi.org/10.3390/biom11071020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301964PMC
July 2021

What's in the BAGs? Intrinsic disorder angle of the multifunctionality of the members of a family of chaperone regulators.

J Cell Biochem 2021 Aug 2. Epub 2021 Aug 2.

Department of Molecular Medicine and Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.

In humans, the family of Bcl-2 associated athanogene (BAG) proteins includes six members characterized by exceptional multifunctionality and engagement in the pathogenesis of various diseases. All of them are capable of interacting with a multitude of often unrelated binding partners. Such binding promiscuity and related functional and pathological multifacetedness cannot be explained or understood within the frames of the classical "one protein-one structure-one function" model, which also fails to explain the presence of multiple isoforms generated for BAG proteins by alternative splicing or alternative translation initiation and their extensive posttranslational modifications. However, all these mysteries can be solved by taking into account the intrinsic disorder phenomenon. In fact, high binding promiscuity and potential to participate in a broad spectrum of interactions with multiple binding partners, as well as a capability to be multifunctional and multipathogenic, are some of the characteristic features of intrinsically disordered proteins and intrinsically disordered protein regions. Such functional proteins or protein regions lacking unique tertiary structures constitute a cornerstone of the protein structure-function continuum concept. The aim of this paper is to provide an overview of the functional roles of human BAG proteins from the perspective of protein intrinsic disorder which will provide a means for understanding their binding promiscuity, multifunctionality, and relation to the pathogenesis of various diseases.
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http://dx.doi.org/10.1002/jcb.30123DOI Listing
August 2021

Liquid-liquid phase separation as a common organizing principle of intracellular space and biomembranes providing dynamic adaptive responses.

Biochim Biophys Acta Mol Cell Res 2021 Oct 20;1868(11):119102. Epub 2021 Jul 20.

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Institutskiy pereulok, 9, Dolgoprudny 141700, Russia; Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., MDC07, Tampa, FL 33612, USA. Electronic address:

This work is devoted to the phenomenon of liquid-liquid phase separation (LLPS), which has come to be recognized as fundamental organizing principle of living cells. We distinguish separation processes with different dimensions. Well-known 3D-condensation occurs in aqueous solution and leads to membraneless organelle (MLOs) formation. 2D-films may be formed near membrane surfaces and lateral phase separation (membrane rafts) occurs within the membranes themselves. LLPS may also occur on 1D structures like DNA and the cyto- and nucleoskeleton. Phase separation provides efficient transport and sorting of proteins and metabolites, accelerates the assembly of metabolic and signaling complexes, and mediates stress responses. In this work, we propose a model in which the processes of polymerization (1D structures), phase separation in membranes (2D structures), and LLPS in the volume (3D structures) influence each other. Disordered proteins and whole condensates may provide membrane raft separation or polymerization of specific proteins. On the other hand, 1D and 2D structures with special composition or embedded IDRs can nucleate condensates. We hypothesized that environmental change may trigger a LLPS which can propagate within the cell interior moving along the cytoskeleton or as an autowave. New phase propagation quickly and using a low amount of energy adjusts cell signaling and metabolic systems to new demands. Cumulatively, the interconnected phase separation phenomena in different dimensions represent a previously unexplored system of intracellular communication and regulation which cannot be ignored when considering both physiological and pathological cell processes.
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http://dx.doi.org/10.1016/j.bbamcr.2021.119102DOI Listing
October 2021

Tudor staphylococcal nuclease is a docking platform for stress granule components and is essential for SnRK1 activation in Arabidopsis.

EMBO J 2021 Sep 21;40(17):e105043. Epub 2021 Jul 21.

Department of Molecular Sciences, Uppsala BioCenter, Swedish University of Agricultural Sciences and Linnean Center for Plant Biology, Uppsala, Sweden.

Tudor staphylococcal nuclease (TSN; also known as Tudor-SN, p100, or SND1) is a multifunctional, evolutionarily conserved regulator of gene expression, exhibiting cytoprotective activity in animals and plants and oncogenic activity in mammals. During stress, TSN stably associates with stress granules (SGs), in a poorly understood process. Here, we show that in the model plant Arabidopsis thaliana, TSN is an intrinsically disordered protein (IDP) acting as a scaffold for a large pool of other IDPs, enriched for conserved stress granule components as well as novel or plant-specific SG-localized proteins. While approximately 30% of TSN interactors are recruited to stress granules de novo upon stress perception, 70% form a protein-protein interaction network present before the onset of stress. Finally, we demonstrate that TSN and stress granule formation promote heat-induced activation of the evolutionarily conserved energy-sensing SNF1-related protein kinase 1 (SnRK1), the plant orthologue of mammalian AMP-activated protein kinase (AMPK). Our results establish TSN as a docking platform for stress granule proteins, with an important role in stress signalling.
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http://dx.doi.org/10.15252/embj.2020105043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447601PMC
September 2021

Computational studies on phylogeny and drug designing using molecular simulations for COVID-19.

J Biomol Struct Dyn 2021 Jul 19:1-10. Epub 2021 Jul 19.

Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.

Since the first appearance of a novel coronavirus pneumonia (NCP) caused by a novel human coronavirus, and especially after the infection started its rapid spread over the world causing the COVID-19 (coronavirus disease 2019) pandemics, a very substantial part of the scientific community is engaged in the intensive research dedicated to finding of the potential therapeutics to cure this disease. As repurposing of existing drugs represents the only instant solution for those infected with the virus, we have been working on utilization of the structure-based virtual screening method to find some potential medications. In this study, we screened a library of 646 FDA approved drugs against the receptor-binding domain of the SARS-CoV-2 spike (S) protein and the main protease of this virus. Scoring functions revealed that some of the anticancer drugs (such as Pazopanib, Irinotecan, and Imatinib), antipsychotic drug (Risperidone), and antiviral drug (Raltegravir) have a potential to interact with both targets with high efficiency. Further we performed molecular dynamics simulations to understand the evolution in protein upon interaction with drug. Also, we have performed a phylogenetic analysis of 43 different coronavirus strains infecting 12 different mammalian species.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1947895DOI Listing
July 2021

Mechanisms of amyloid proteins aggregation and their inhibition by antibodies, small molecule inhibitors, nano-particles and nano-bodies.

Int J Biol Macromol 2021 Sep 14;186:580-590. Epub 2021 Jul 14.

Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.

Protein misfolding and aggregation can be induced by a wide variety of factors, such as dominant disease-associated mutations, changes in the environmental conditions (pH, temperature, ionic strength, protein concentration, exposure to transition metal ions, exposure to toxins, posttranslational modifications including glycation, phosphorylation, and sulfation). Misfolded intermediates interact with similar intermediates and progressively form dimers, oligomers, protofibrils, and fibrils. In amyloidoses, fibrillar aggregates are deposited in the tissues either as intracellular inclusion or extracellular plaques (amyloid). When such proteinaceous deposit occurs in the neuronal cells, it initiates degeneration of neurons and consequently resulting in the manifestation of various neurodegenerative diseases. Several different types of molecules have been designed and tested both in vitro and in vivo to evaluate their anti-amyloidogenic efficacies. For instance, the native structure of a protein associated with amyloidosis could be stabilized by ligands, antibodies could be used to remove plaques, oligomer-specific antibody A11 could be used to remove oligomers, or prefibrillar aggregates could be removed by affibodies. Keeping the above views in mind, in this review we have discussed protein misfolding and aggregation, mechanisms of protein aggregation, factors responsible for aggregations, and strategies for aggregation inhibition.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.07.056DOI Listing
September 2021

Networks of Networks: An Essay on Multi-Level Biological Organization.

Front Genet 2021 21;12:706260. Epub 2021 Jun 21.

Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy.

The multi-level organization of nature is self-evident: proteins do interact among them to give rise to an organized metabolism, while in the same time each protein (a single node of such interaction network) is itself a network of interacting amino-acid residues allowing coordinated motion of the macromolecule and systemic effect as allosteric behavior. Similar pictures can be drawn for structure and function of cells, organs, tissues, and ecological systems. The majority of biologists are used to think that causally relevant events originate from the lower level (the molecular one) in the form of perturbations, that "climb up" the hierarchy reaching the ultimate layer of macroscopic behavior (e.g., causing a specific disease). Such causative model, stemming from the usual genotype-phenotype distinction, is not the only one. As a matter of fact, one can observe top-down, bottom-up, as well as middle-out perturbation/control trajectories. The recent complex network studies allow to go further the pure qualitative observation of the existence of both non-linear and non-bottom-up processes and to uncover the deep nature of multi-level organization. Here, taking as paradigm protein structural and interaction networks, we review some of the most relevant results dealing with between networks communication shedding light on the basic principles of complex system control and dynamics and offering a more realistic frame of causation in biology.
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http://dx.doi.org/10.3389/fgene.2021.706260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255927PMC
June 2021

Evaluation of ThT augmentation and RLS inner filter effect caused by highly fluorescent coumarin derivative and establishing it as true inhibitor of amyloid fibrillation.

Arch Biochem Biophys 2021 09 30;709:108981. Epub 2021 Jun 30.

Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, 202002, India. Electronic address:

Screening of inhibitors that slow down or suppress amyloid fibrils formation relies on some simple but sensitive spectroscopy techniques. Thioflavin T (ThT) fluorescence assay is one of the most common, amyloid specific and sensitive method. However, if an inhibitor is itself fluorescent in the ThT fluorescence range, its screening becomes complicated and require complementary assays. One of such molecules, 6, 7-dihydroxycoumarin (6, 7-DHC, also known as aesculetin, esculetin, and cichorigenin) is fluorescent in the ThT emission range and absorbs in the ThT excitation range. Therefore, it can produce a subtractive effect attributed to primary inner filter effect and/or additive effect due to its self-fluorescence in ThT assay. Our study shows that 6, 7-DHC produces an additive effect in ThT fluorescence, which is minimized at high concentration of ThT and decrease in ThT fluorescence is solely due to its inhibitory effect against HSA fibrillation. These ThT fluorescence-based results are verified through other complementary assays, such as Rayleigh and dynamic light scattering and amyloid-specific Congo red binding assay. Furthermore, hydrophobicity reduction is studied through Nile red (NR) and kinetics through far-UV circular dichroism (far-UV CD) in place of the most commonly employed ThT assay owing to extremely high fluorescence of 6, 7-DHC during initial incubation period.
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http://dx.doi.org/10.1016/j.abb.2021.108981DOI Listing
September 2021

Analysis of the dark proteome of Chandipura virus reveals maximum propensity for intrinsic disorder in phosphoprotein.

Sci Rep 2021 06 24;11(1):13253. Epub 2021 Jun 24.

School of Basic Sciences, Indian Institute of Technology Mandi, VPO Kamand, Kamand, Himachal Pradesh, 175005, India.

Chandipura virus (CHPV, a member of the Rhabdoviridae family) is an emerging pathogen that causes rapidly progressing influenza-like illness and acute encephalitis often leading to coma and death of the human host. Given several CHPV outbreaks in Indian sub-continent, recurring sporadic cases, neurological manifestation, and high mortality rate of this infection, CHPV is gaining global attention. The 'dark proteome' includes the whole proteome with special emphasis on intrinsically disordered proteins (IDP) and IDP regions (IDPR), which are proteins or protein regions that lack unique (or ordered) three-dimensional structures within the cellular milieu. These proteins/regions, however, play a number of vital roles in various biological processes, such as cell cycle regulation, control of signaling pathways, etc. and, therefore, are implicated in many human diseases. IDPs and IPPRs are also abundantly found in many viral proteins enabling their multifunctional roles in the viral life cycles and their capability to highjack various host systems. The unknown abundance of IDP and IDPR in CHPV, therefore, prompted us to analyze the dark proteome of this virus. Our analysis revealed a varying degree of disorder in all five CHPV proteins, with the maximum level of intrinsic disorder propensity being found in Phosphoprotein (P). We have also shown the flexibility of P protein using extensive molecular dynamics simulations up to 500 ns (ns). Furthermore, our analysis also showed the abundant presence of the disorder-based binding regions (also known as molecular recognition features, MoRFs) in CHPV proteins. The identification of IDPs/IDPRs in CHPV proteins suggests that their disordered regions may function as potential interacting domains and may also serve as novel targets for disorder-based drug designs.
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http://dx.doi.org/10.1038/s41598-021-92581-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225862PMC
June 2021

Understanding structural malleability of the SARS-CoV-2 proteins and relation to the comorbidities.

Brief Bioinform 2021 Jun 18. Epub 2021 Jun 18.

Department of Computer Science and Engineering, Jadavpur University, Kolkata-32, West Bengal, India.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of the coronavirus disease (COVID-19), is a part of the $\beta $-Coronaviridae family. The virus contains five major protein classes viz., four structural proteins [nucleocapsid (N), membrane (M), envelop (E) and spike glycoprotein (S)] and replicase polyproteins (R), synthesized as two polyproteins (ORF1a and ORF1ab). Due to the severity of the pandemic, most of the SARS-CoV-2-related research are focused on finding therapeutic solutions. However, studies on the sequences and structure space throughout the evolutionary time frame of viral proteins are limited. Besides, the structural malleability of viral proteins can be directly or indirectly associated with the dysfunctionality of the host cell proteins. This dysfunctionality may lead to comorbidities during the infection and may continue at the post-infection stage. In this regard, we conduct the evolutionary sequence-structure analysis of the viral proteins to evaluate their malleability. Subsequently, intrinsic disorder propensities of these viral proteins have been studied to confirm that the short intrinsically disordered regions play an important role in enhancing the likelihood of the host proteins interacting with the viral proteins. These interactions may result in molecular dysfunctionality, finally leading to different diseases. Based on the host cell proteins, the diseases are divided in two distinct classes: (i) proteins, directly associated with the set of diseases while showing similar activities, and (ii) cytokine storm-mediated pro-inflammation (e.g. acute respiratory distress syndrome, malignancies) and neuroinflammation (e.g. neurodegenerative and neuropsychiatric diseases). Finally, the study unveils that males and postmenopausal females can be more vulnerable to SARS-CoV-2 infection due to the androgen-mediated protein transmembrane serine protease 2.
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http://dx.doi.org/10.1093/bib/bbab232DOI Listing
June 2021

An emerging role for BAG3 in gynaecological malignancies.

Br J Cancer 2021 Sep 7;125(6):789-797. Epub 2021 Jun 7.

Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, Baronissi, SA, Italy.

BAG3, a member of the BAG family of co-chaperones, is a multidomain protein with a role in several cellular processes, including the control of apoptosis, autophagy and cytoskeletal dynamics. The expression of bag3 is negligible in most cells but can be induced by stress stimuli or malignant transformation. In some tumours, BAG3 has been reported to promote cell survival and resistance to therapy. The expression of BAG3 has been documented in ovarian, endometrial and cervical cancers, and studies have revealed biochemical and functional connections of BAG3 with proteins involved in the survival, invasion and resistance to therapy of these malignancies. BAG3 expression has also been shown to correlate with the grade of dysplasia in squamous intraepithelial lesions of the uterine cervix. Some aspects of BAG3 activity, such as its biochemical and functional interaction with the human papillomavirus proteins, could help in our understanding of the mechanisms of oncogenesis induced by the virus. This review aims to highlight the potential value of BAG3 studies in the field of gynaecological tumours.
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http://dx.doi.org/10.1038/s41416-021-01446-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437940PMC
September 2021

Serotonin Promotes Serum Albumin Interaction with the Monomeric Amyloid β Peptide.

Int J Mol Sci 2021 May 31;22(11). Epub 2021 May 31.

Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia.

Prevention of amyloid β peptide (Aβ) deposition via facilitation of Aβ binding to its natural depot, human serum albumin (HSA), is a promising approach to preclude Alzheimer's disease (AD) onset and progression. Previously, we demonstrated the ability of natural HSA ligands, fatty acids, to improve the affinity of this protein to monomeric Aβ by a factor of 3 (BBRC, 510(2), 248-253). Using plasmon resonance spectroscopy, we show here that another HSA ligand related to AD pathogenesis, serotonin (SRO), increases the affinity of the Aβ monomer to HSA by a factor of 7/17 for Aβ/Aβ, respectively. Meanwhile, the structurally homologous SRO precursor, tryptophan (TRP), does not affect HSA's affinity to monomeric Aβ, despite slowdown of the association and dissociation processes. Crosslinking with glutaraldehyde and dynamic light scattering experiments reveal that, compared with the TRP-induced effects, SRO binding causes more marked changes in the quaternary structure of HSA. Furthermore, molecular docking reveals distinct structural differences between SRO/TRP complexes with HSA. The disintegration of the serotonergic system during AD pathogenesis may contribute to Aβ release from HSA in the central nervous system due to impairment of the SRO-mediated Aβ trapping by HSA.
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http://dx.doi.org/10.3390/ijms22115896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199245PMC
May 2021

The Role of Non-Specific Interactions in Canonical and ALT-Associated PML-Bodies Formation and Dynamics.

Int J Mol Sci 2021 May 29;22(11). Epub 2021 May 29.

Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Ave., 194064 St. Petersburg, Russia.

In this work, we put forward a hypothesis about the decisive role of multivalent nonspecific interactions in the early stages of PML body formation. Our analysis of the PML isoform sequences showed that some of the PML isoforms, primarily PML-II, are prone to phase separation due to their polyampholytic properties and the disordered structure of their C-terminal domains. The similarity of the charge properties of the C-terminal domains of PML-II and PML-VI isoforms made it possible for the first time to detect migration of PML-VI from PML bodies to the periphery of the cell nucleus, similar to the migration of PML-II isoforms. We found a population of "small" (area less than 1 µm) spherical PML bodies with high dynamics of PML isoforms exchange with nucleoplasm and a low fraction of immobilized proteins, which indicates their liquid state properties. Such structures can act as "seeds" of functionally active PML bodies, providing the necessary concentration of PML isoforms for the formation of intermolecular disulfide bonds between PML monomers. FRAP analysis of larger bodies of toroidal topology showed the existence of an insoluble scaffold in their structure. The hypothesis about the role of nonspecific multiple weak interactions in the formation of PML bodies is further supported by the change in the composition of the scaffold proteins of PML bodies, but not their solidification, under conditions of induction of dimerization of PML isoforms under oxidative stress. Using the colocalization of ALT-associated PML bodies (APBs) with TRF1, we identified APBs and showed the difference in the dynamic properties of APBs and canonical PML bodies.
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http://dx.doi.org/10.3390/ijms22115821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198325PMC
May 2021
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