Biology subjects

Uversky, V. N.

Publications and source records attributed to Uversky, V. N..

34 records · Page 2Linked to original sources

bioRxiv2023

SARS-CoV-2 NSP14 governs mutational instability and assists in making new SARS-CoV-2 variants

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the rapidly evolving RNA virus behind the COVID-19 pandemic, has spawned numerous variants since its 2019 emergence. The multifunctional NSP14 enzyme, possessing exonuclease and mRNA capping capabilities, serves as a key player. Notably, single and co-occurring mutations within NSP14 significantly influence replication fidelity and drive variant diversification. This study comprehensively examines 120 co-mutations, 68 unique mutations, and 160 conserved residues across NSP14 homologs, shedding light on their implications for phylogenetic patterns, pathogenicity, and residue interactions. Quantitative physicochemical analysis categorizes 3953 NSP14 variants into three clusters, revealing genetic diversity. This research underscores the dynamic nature of SARS-CoV-2 evolution, primarily governed by NSP14 mutations. Understanding these genetic dynamics provides valuable insights for therapeutic and vaccine development.

bioinformatics↗

bioRxiv2023

Chaotic aging: Intrinsically disordered proteins in aging-related processes

1.The development of aging is associated with the disruption of key cellular processes manifested as well-established hallmarks of aging. Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) have no stable tertiary structure that provide them a power to be configurable hubs in signaling cascades and regulate many processes, potentially including those related to aging. There is a need to clarify the roles of IDPs/IDRs in aging. The dataset of 1624 aging-related proteins was collected from established aging databases and experimental studies. There is a noticeable presence of IDPs/IDRs, accounting for about 36% of the aging-related dataset, which is comparable to the disorder content of the whole human proteome (about 40%). A Gene Ontology analysis of the our Aging proteome reveals an abundance of IDPs/IDRs in one-third of aging-associated processes, especially in genome regulation. Signaling pathways associated with aging also contain IDPs/IDRs on different hierarchical levels. Protein-protein interaction network analysis showed that IDPs present in different clusters associated with different aging hallmarks. Protein cluster with IDPs enrichment and high liquid-liquid phase separation (LLPS) probability has "nuclear" localization and DNA-associated functions, related to aging hallmarks: genomic instability, telomere attrition, epigenetic alterations, stem cells exhaustion. Some IDPs related to aging with high LLPS propensity were identified as "dangerous" based on the prediction of their propensity to aggregation. Overall, our analyses indicate that IDPs/IDRs play significant roles in aging-associated processes, particularly in the regulation of DNA functioning. IDP aggregation, which can lead to loss-of-function and toxicity, could be critically harmful to the cell. A structure-based analysis of aging and the identification of proteins that are particularly susceptible to disturbances can enhance our understanding of the molecular mechanisms of aging and open up new avenues for slowing it down.

bioinformatics↗

bioRxiv2023

Biology of Coital Behavior: Looking Through the Lens of Mathematical Genomics

Research has shown that genetics and epigenetics regulate mating behavior across multiple species. Previous studies have generally focused on the signaling pathways involved and spatial distribution of the associated receptors. However a thorough quantitative characterization of the receptors involved may offer deeper insight into mating behavioral patterns. Here oxytocin, arginine-vasopressin 1a, dopamine 1, and dopamine 2 receptors were investigated across 76 vertebrate species. The receptor sequences were characterized by polarity-based randomness, amino acid frequency-based Shannon entropy and Shannon sequence variability, intrinsic protein disorder, binding affinity, stability and pathogenicity of homology-based SNPs, structural and physicochemical features. Hierarchical clustering of species was derived based on structural and physicochemical features of the four receptor sequences separately, which eventually led to proximal relationships among 29 species. Humans were found to be significantly distant phylogenetically from the prairie voles, a representative of monogamous species based on coital behavior. Furthermore, the mouse (polygamous), the prairie deer mouse (polygamous), and the prairie vole (monogamous) although being proximally related (based on quantitative genomics of receptors), differed in their coital behavioral pattern, mostly, due to behavioral epigenetic regulations. This study adds a perspective that receptor genomics does not directly translate to behavioral patterns.

genomics↗

bioRxiv2022

Ribosomal protein with conserved function has entirely different structures in different organisms

Ribosomes from different species can markedly differ in their composition by including dozens of ribosomal proteins that are unique to specific lineages but absent in others. However, it remains unknown how ribosomes acquire and specialize new proteins throughout evolution. Here, to help answer this question, we describe the evolution of the ribosomal protein msL1/msL2 that was recently found in ribosomes from the parasitic microorganism clade, microsporidia. We first show that this protein has a conserved location in the ribosome but entirely dissimilar structures in different organisms: in each of the analyzed species, msL1/msL2 exhibits an altered secondary structure, an inverted orientation of the N- and C-termini on the ribosomal binding surface, and a completely transformed three-dimensional fold. We then show that this evolutionary fold switching is likely caused by changes in the msL1/msL2-binding site in the ribosome; specifically, by variations in microsporidian rRNA. These observations allow us to infer an evolutionary scenario in which a small, positively-charged, de novo-born unfolded protein was first captured by rRNA to become part of the ribosome and subsequently underwent complete fold switching to optimize its binding to its evolving ribosomal binding site. Overall, our work provides a striking example of how a protein can switch its fold in the context of a complex biological assembly while retaining its specificity for its molecular partner. This finding will help us better understand the origin and evolution of new protein components of complex molecular assemblies - thereby enhancing our ability to engineer biological molecules, identify protein homologs, and peer into the history of life on Earth.

evolutionary biology↗

bioRxiv2022

Possible Functional Proximity of Various Organisms Based on Taste Receptors Genomics

Taste is one of the essential senses in providing the organism a faithful representation of the external world. Taste perception is responsible for basic food and drink appraisal and bestows the organism with valuable discriminatory power. Umami and sweet are "good" tastes that promote consumption of nutritive food, whereas bitter and sour are "bad" tastes that alert the organism to toxins and low pH, promoting rejection of foods containing harmful substances. Not every animal has the same sense of taste as humans. Variation in the taste receptor genes contributes to inter and intra organism differences of taste (sweet/bitter) sensation and preferences. Therefore a deeper understanding was needed to comprehend taste perception by various vertebrates and accordingly elucidate a possible proximity among them. In this study, a total 20 Type-1 (sweet) and 189 Type-2 (bitter) taste receptor complete-amino acid sequences were taken from the 20 vertebrate organisms (18 mammalian, 1 aves, and 1 amphibian). Among 10 primates, 8 including humans were very close based on genomics of taste receptors and rodent organisms viz. the rat and mouse were away from them. This investigation throws light on the similitude and dissimilitude of perception of sweet and bitter taste among 20 different organisms, steered by quantitative analysis of their genomic data. Furthermore, it enlightened that ligand binding affinity of sweet/bitter taste molecules in the taste receptors of any proximal pair of organisms would be similar.

genomics↗

bioRxiv2022

SARS-CoV-2 variants show a gradual declining pathogenicity and pro-inflammatory cytokine stimulation and an increasing antigenic and anti-inflammatory cytokine induction

Hyper-transmissibility with decreased disease severity are typical characteristics of Omicron variant. To understand this phenomenon, we used various bioinformatics approaches to analyze randomly selected genome sequences (one each) of the Gamma, Delta, and Omicron variants submitted to NCBI from 15 to 31 December 2021. We show that: (i) Pathogenicity of SARS-CoV-2 variants decreases in the order: Wuhan > Gamma > Delta > Omicron; however, the antigenic property follows the order: Omicron > Gamma > Wuhan > Delta. (ii) Omicron Spike RBD has lower pathogenicity but higher antigenicity than other variants. (iii) Decreased disease severity by Omicron variant may be due to its decreased pro-inflammatory and IL-6 stimulation and increased IFN-{gamma} and IL-4 induction efficacy. (iv) Mutations in N protein are associated with decreased IL-6 induction and human DDX21-mediated increased IL-4 production in Omicron. (v) Due to mutations, the stability of S, M, N, and E proteins decreases in the order: Omicron > Gamma > Delta > Wuhan. (vi) Stronger Spike RBD-hACE2 binding in Omicron is associated with increased transmissibility. However, the lowest stability of the Omicron Spike protein makes Spike RBD-hACE2 interaction weak for systemic infection and for causing severe disease. Finally (vii), the highest instability of Omicron E protein may also be associated with decreased viral maturation and low viral load leading to less severe disease and faster recovery. Our method may be used for other similar viruses, and these findings will contribute to the understanding of the dynamics of SARS-CoV-2 variants and the management of emerging variants.

bioinformatics↗

bioRxiv2022

A novel consensus-based computational pipeline for rapid screening of antibody therapeutics for efficacy against SARS-CoV-2 variants of concern including omicron variant

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to evolve carrying flexible amino acid substitutions in the spike proteins receptor binding domain (RBD). These substitutions modify the binding of the SARS-CoV-2 to human angiotensin-converting enzyme 2 (hACE2) receptor and have been implicated in altered host fitness, transmissibility and efficacy against antibody therapeutics and vaccines. Reliably predicting the binding strength of SARS-CoV-2 variants RBD to hACE2 receptor and neutralizing antibodies (NAbs) can help assessing their fitness, and rapid deployment of effective antibody therapeutics, respectively. Here, we introduced a two-step computational framework with three-fold validation that first identified dissociation constant as a reliable predictor of binding affinity in hetero-dimeric and -trimeric protein complexes. The second step implements dissociation constant as descriptor of the binding strengths of SARS-CoV-2 variants RBD to hACE2 and NAbs. Then, we examined several variants of concern (VOCs) such as Alpha, Beta, Gamma, Delta, and Omicron and demonstrated that these VOCs RBD bind to the hACE2 with enhanced affinity. Furthermore, the binding affinity of Omicron variants RBD was reduced with majority of the RBD-directed NAbs, which is highly consistent with the experimental neutralization data. By studying the atomic contacts between RBD and NAbs, we revealed the molecular footprints of four NAbs (GH-12, P2B-1A1, Asarnow_3D11, and C118) -- that may likely neutralize the recently emerged omicron variant -- facilitating enhanced binding affinity. Finally, our findings suggest a computational pathway that could aid researchers identify a range of current NAbs that may be effective against emerging SARS-CoV-2 variants.

bioinformatics↗

bioRxiv2021

An Issue of Concern: Unique Truncated ORF8 Protein Variants of SARS-CoV-2

Open reading frame 8 (ORF8) protein is one of the most evolving accessory proteins in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). It was previously reported that the ORF8 protein inhibits presentation of viral antigens by the major histocompatibility complex class I (MHC-I) and interacts with host factors involved in pulmonary inflammation. The ORF8 protein assists SARS-CoV-2 to evade immunity and replication. Among many contributing mutations, Q27STOP, a mutation in the ORF8 protein defines the B.1.1.7 lineage of SARS-CoV-2, which is engendering the second wave of COVID-19. In the present study, 47 unique truncated ORF8 proteins (T-ORF8) due to the Q27STOP mutations were identified among 49055 available B.1.1.7 SARS-CoV-2 sequences. The results show that only one of the 47 T-ORF8 variants spread to over 57 geo-locations in North America, and other continents which includes Africa, Asia, Europe and South America. Based on various quantitative features such as amino acid homology, polar/non-polar sequence homology, Shannon entropy conservation, and other physicochemical properties of all specific 47 T-ORF8 protein variants, a collection of nine possible T-ORF8 unique variants were defined. The question of whether T-ORF8 variants work similarly to ORF8 has yet to be investigated. A positive response to the question could exacerbate future COVID-19 waves, necessitating severe containment measures.

bioinformatics↗

bioRxiv2021

Implications Derived from S-Protein Variants of SARS-CoV-2 from Six Continents

Spike (S) proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are critical determinants of the infectivity and antigenicity of the virus. Several mutations in the spike 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, spike 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 (29.065%) had the highest percentage of unique S proteins. Notably, only North America had 87% (14046) of the total (16143) specific S proteins available in the NCBI database(across all continents). Based on the amino acid frequency distributions in the S protein variants from all the continents, the phylogenetic relationship implies that unique S proteins from North America were significantly different from those of the other five continents. Overtime, the unique variants originating from North America are most likely to spread to the other geographic locations through international travel or naturally by emerging mutations. Hence it is suggested that restriction of international travel should be considered, and massive vaccination as an utmost measure to combat the spread of 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.

bioinformatics↗

bioRxiv2020

Variability of Accessory Proteins Rules the SARS-CoV-2 Pathogenicity

The coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) which is pandemic with an estimated fatality rate less than 1% is ongoing. SARS-CoV-2 accessory proteins ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10 with putative functions to manipulate host immune mechanisms such as interferons, immune signaling receptor NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) inflammasome, inflammatory cytokines such as interleukin 1{beta} (IL-1{beta}) are critical in COVID-19 pathology. Outspread variations of each of the six accessory proteins of all complete proteomes (available as of October 26, 2020, in the National Center for Biotechnology Information depository) of SARS-CoV-2, were observed across six continents. Across all continents, the decreasing order of percentage of unique variations in the accessory proteins was found to be ORF3a>ORF8>ORF7a>ORF6>ORF10>ORF7b. The highest and lowest unique variations of ORF3a were observed in South America and Oceania, respectively. This finding suggests that the wide variations of accessory proteins seem to govern the pathogenicity of SARS-CoV-2, and consequently, certain propositions and recommendations can be made in the public interest.

bioinformatics↗

bioRxiv2020

Possible transmission flow of SARS-CoV-2 based on ACE2 features

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22-42, aa 79-84, and aa 330-393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.

bioinformatics↗

bioRxiv2020

Notable sequence homology of the ORF10 protein introspects the architecture of SARS-COV-2

The global public health is endangered due to COVID-19 pandemic, which is caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Despite having similar pathology to MERS and SARS-CoV, the infection fatality rate of SARS-CoV-2 is likely lower than 1%. SARS-CoV-2 has been reported to be uniquely characterized by the accessory protein ORF10, which contains eleven cytotoxic T lymphocyte (CTL) epitopes of nine amino acids length each, across various human leukocyte antigen (HLA) subtypes. In this study, all missense mutations found in sequence databases were examined across twnety-two unique SARS-CoV-2 ORF10 variants that could possibly alter viral pathogenicity. Some of these mutations decrease the stability of ORF10, e.g. I4L and V6I were found in the MoRF region of ORF10 which may also possibly contribute to Intrinsic protein disorder. Furthermore, a physicochemical and structural comparative analysis was carried out on SARS-CoV-2 and Pangolin-CoV ORF10 proteins, which share 97.37% amino acid homology. The high degree of physicochemical and structural similarity of ORF10 proteins of SARS-CoV-2 and Pangolin-CoV open questions about the architecture of SARS-CoV-2 due to the disagreement of these two ORF10 proteins over their sub-structure (loop/coil region), solubility, antigenicity and change from the strand to coil at amino acid position 26, where tyrosine is present. Altogether, SARS-CoV-2 ORF10 is a promising pharmaceutical target and a protein which should be monitored for changes which correlate to change pathogenesis and clinical course of COVID-19 infection.

bioinformatics↗

bioRxiv2020

A unique view of SARS-CoV-2 through the lens of ORF8 protein

Immune evasion is one of the unique characteristics of COVID-19 attributed to the ORF8 protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This protein is involved in modulating the host adaptive immunity through downregulating MHC (Major Histocompatibility Complex) molecules and innate immune responses by surpassing the interferon mediated antiviral response of the host. To understand the immune perspective of the host with respect to the ORF8 protein, a comprehensive study of the ORF8 protein as well as mutations possessed by it, is performed. Chemical and structural properties of ORF8 proteins from different hosts, that is human, bat and pangolin, suggests that the ORF8 of SARS-CoV-2 and Bat RaTG13-CoV are very much closer related than that of Pangolin-CoV. Eighty-seven mutations across unique variants of ORF8 (SARS-CoV-2) are grouped into four classes based on their predicted effects. Based on geolocations and timescale of collection, a possible flow of mutations was built. Furthermore, conclusive flows of amalgamation of mutations were endorsed upon sequence similarity and amino acid conservation phylogenies. Therefore, this study seeks to highlight the uniqueness of rapid evolving SARS-CoV-2 through the ORF8.

molecular biology↗

bioRxiv2020

An exploration of the SARS-CoV-2 spike receptor binding domain (RBD), a complex palette of evolutionary and structural features

SARS-CoV-2 spike protein (S) is associated with the entry of virus inside the host cell by recruiting its loop dominant receptor binding domain (RBD) and interacting with the host ACE2 receptor. Our study deploying a two-tier approach encompassing evolutionary and structural analysis provides a comprehensive picture of the RBD, which could be of potential use for better understanding the RBD and address its druggability issues. Resorting to an ensemble of sequence space exploratory tools including co-evolutionary analysis and deep mutational scans we provide a quantitative insight into the evolutionarily constrained subspace of the RBD sequence space. Guided by structure network analysis and Monte Carlo simulation we highlight regions inside the RBD, which are critical for providing structural integrity and conformational flexibility of the binding cleft. We further deployed fuzzy C-means clustering by plugging the evolutionary and structural features of discrete structure blocks of RBD to understand which structure blocks share maximum overlap based on their evolutionary and structural features. Deploying this multi-tier interlinked approach, which essentially distilled the evolutionary and structural features of RBD, we highlight discrete region, which could be a potential druggable pocket thereby destabilizing the structure and addressing evolutionary routes.

biophysics↗

bioRxiv2020

Tudor staphylococcal nuclease acts as a docking platform for stress granule components in Arabidopsis thaliana

Adaptation to stress depends on the modulation of gene expression. Regulation of mRNA stability and degradation in stress granules (SGs), - cytoplasmic membraneless organelles composed of messenger ribonucleoprotein (mRNP) complexes, - plays an important role in fine-tuning of gene expression. In addition, SG formation can modulate stress signaling pathways by protein sequestration. Molecular composition, structure, and function of SGs in plants remain obscure. Recently, we established Tudor Staphylococcal Nuclease (TSN or Tudor-SN; also known as SND1) as integral component of SGs in Arabidopsis thaliana. Here, we combined purification of TSN interactome with cell biology, reverse genetics and bioinformatics to study composition and function of SGs in plants. We found that under both normal (in the absence of stress) and stress conditions TSN interactome is enriched in the homologues of known mammalian and yeast SG proteins, in addition to novel or plant-specific SG components. We estimate that upon stress perception, approximately half of TSN interactors are recruited to SGs de novo, in a stress-dependent manner, while another half represent a dense protein-protein interaction network pre-formed before onset of stress. Almost all TSN-interacting proteins are moderately or highly disordered and approximately 20% of them are predisposed for liquid-liquid phase separation (LLPS). This suggests that plant SGs, similarly to mammalian and yeast counterparts, are multicomponent viscous liquid droplets. Finally, we have discovered that evolutionary conserved SNF1-related protein kinase 1 (SnRK1) interacts with TSN in heat-induced SGs and that SnRK1 activation critically depends on the presence of TSN and formation of SGs. Altogether, our results establish TSN as a docking platform for SG-associated proteins and important stress signal mediator in plants.

plant biology↗

bioRxiv2019

Granulins modulate liquid-liquid phase separation and aggregation of TDP-43 C-terminal domain

Tar DNA binding protein (TDP-43) has emerged as a key player in many neurodegenerative pathologies including frontotemporal lobar degeneration (FTLD) and amyotropic lateral sclerosis (ALS). Important hallmarks of FTLD and ALS are the toxic cytoplasmic inclusions of C-terminal fragments of TDP-43 (TDP-43CTD), which are formed upon proteolytic cleavage of full-length TDP-43 in the nucleus and subsequent transport to the cytoplasm. TDP-43CTD is also known to form stress granules (SGs) by coacervating with RNA in cytoplasm under stress conditions and are believed to be involved in modulating the pathologies. Among other factors affecting these pathologies, the pleiotropic protein called progranulin (PGRN) has gained significant attention lately. The haploinsufficiency of PGRN, caused by autosomal dominant mutations in GRN gene, results in its loss-of-function linked to FTLD and ALS. But precisely how the protein contributes to the pathology remains unknown. Recently, cleavage to GRNs were observed to be a significant part of FTLD and ALS progression with specific GRNs exacerbating TDP-43-induced toxicity in C.elegans. In this report, we show that GRNs -3 and -5 directly interact with TDP-43CTD to modulate latters aggregation or stress granule formation in disparate ways in vitro. These results constitute the first observation of direct interaction between GRNs and TDP-43 and suggest a mechanism by which the loss of PGRN function could lead to FTLD and ALS.

biophysics↗