Medicine and Health Sciences | Open Access Articles

Recombinant Fusion Protein Joining E Protein Domain Iii Of Tick-Borne Encephalitis Virus And Hsp70 Of Yersinia Pseudotuberculosis As An Antigen For The Ti-Complexes, Vasily Golotin, Nina M. Sanina, Ludmila Davydova, Natalia Chopenko, Andrey Mazeika, Manuel Roig, Valery L. Shnyrov, Vladimir N. Uversky, Eduard Kostetsky

Molecular Medicine Faculty Publications

Domain III (DIII) of the tick-borne encephalitis virus (TBEV) protein E contains epitopes, which induce antibodies capable of neutralizing the virus. To enhance the immunogenicity of this protein, which has a low molecular weight, the aim of the present work was to express, isolate, and characterize a chimeric protein based on the fusion of the bacterial chaperone HSP70 of Yersinia pseudotuberculosis and EIII (DIII + stem) as a prospective antigen for an adjuvanted delivery system, the tubular immunostimulating complex (TI-complex). The chimeric construction was obtained using pET-40b(+) vector by ligating the respective genes. The resulting plasmid was transformed into DE3 …

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Prediction Of Disordered Regions And Their Roles In The Anti-Pathogenic And Immunomodulatory Functions Of Butyrophilins, Elrashdy M. Redwan, Ahmed M. Al-Hejin, Hussein A. Almehdar, Abdulrahman Elsaway, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Butyrophilins (BTNs) are a group of the moonlighting proteins, some members of which are secreted in milk. They constitute a large family of structurally similar type 1 transmembrane proteins from the immunoglobulin superfamily. Although the founding member of this family is related to lactation, participating in the secretion, formation and stabilization of milk fat globules, it may also have a cell surface receptor function. Generally, the BTN family members are known to modulate co-stimulatory responses, T cell selection, differentiation, and cell fate determination. Polymorphism of these genes was shown to be associated with the pathology of several human diseases. Despite …

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Immunogenicity And Protective Activity Of A Chimeric Protein Based On The Domain Iii Of The Tick-Borne Encephalitis Virus E Protein And The Ompf Porin Of Yersinia Pseudotuberculosis Incorporated Into The Ti-Complex, Nina M. Sanina, Natalia Chopenko, Andrey Mazeika, Ludmila Davydova, Galina Leonova, Anna Stenkova, Vladimir N. Uversky, Eduard Kostetsky

Molecular Medicine Faculty Publications

Tick-borne encephalitis (TBE) is a widespread, dangerous infection. Unfortunately, all attempts to create safe anti-TBE subunit vaccines are still unsuccessful due to their low immunogenicity. The goal of the present work was to investigate the immunogenicity of a recombinant chimeric protein created by the fusion of the EIII protein, comprising domain III and a stem region of the tick-borne encephalitis virus (TBEV) E protein, and the OmpF porin of Yersinia pseudotuberculosis (OmpF-EIII). Adjuvanted antigen delivery systems, the tubular immunostimulating complexes (TI-complexes) based on the monogalactosyldiacylglycerol from different marine macrophytes, were used to enhance the immunogenicity of OmpF-EIII. Also, the chimeric …

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Intrinsically Disordered Proteins And The Janus Challenge, Prakash Kulkarni, Vladimir N. Uversky

Molecular Medicine Faculty Publications

To gain a new insight into the role of proteins in the origin of life on Earth, we present the Janus Challenge: identify an intrinsically disordered protein (IDP), naturally occurring or synthetic, that has catalytic activity. For example, such a catalytic IDP may perform condensation reactions to catalyze a peptide bond or a phosphodiester bond formation utilizing natural/un-natural amino acids or nucleotides, respectively. The IDP may also have autocatalytic, de novo synthesis, or self-replicative activity. Meeting this challenge may not only shed new light and provide an alternative to the RNA world hypothesis, but it may also serve as an …

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Understanding The Interactability Of Chikungunya Virus Proteins Via Molecular Recognition Feature Analysis, Ankur Singh, Ankur Kumar, Vladimir N. Uversky, Rajanish Giri

Molecular Medicine Faculty Publications

The chikungunya virus (CHIKV) is an alphavirus that has an enveloped icosahedral capsid and is transmitted by Aedes sp. mosquitos. It contains four non-structural proteins, namely nsP1, nsP2, nsP3, and nsP4, encoded at the 5′ end of the genome, and five structural proteins encoded at the 3′ end of the genome, including three glycosylated proteins, namely E1, E2, E3, a small 64 amino-acids glycoprotein 6K, and one non-glycosylated nucleocapsid protein C. The surface of this positive-stranded RNA alphavirus is covered with 80 trimeric glycoprotein spikes, which facilitate viral access into the host cell, with each consisting of three copies of …

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Elucidating Feed‑Forward Apoptosis Signatures In Breast Cancer Datasets: Higher Fos Expression Associated With A Better Outcome, Diana A. Fisler, Dhiraj Sikaria, John M. Yavorski, Yaping N. Tu, George Blanck

Molecular Medicine Faculty Publications

Overstimulation of pro‑proliferative pathways and high level expression of pro‑proliferative transcription factors (TFs) can lead to apoptosis. This is likely due to TF binding sites for pro‑proliferative TFs common to pro‑proliferative and pro‑apoptosis‑effector genes. Certain clinical datasets have indicated that molecular markers associated with higher proliferation rates lead to improved outcomes for patients with cancer. These observations have been extensively assessed on a general basis, however there has been little work dissecting feed‑forward apoptosis signaling pathways that may represent specific distinctions between a pro‑proliferative mechanism and a pro‑apoptotic mechanism in samples from patients with cancer. Using The Cancer Genome Atlas …

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Oxidative Stress Induces Club Cell Proliferation And Pulmonary Fibrosis In Atp8b1 Mutant Mice, Jutaro Fukumoto, Joseph Leung, Ruan Cox Jr, Alexander Czachor, Prasanna Tamarapu Parthasarathy, Venu Lagishetty, Maria Mandry, Nima Hosseinian, Priyanshi Patel, Brittany Perry, Mason T. Breitzig, Matthew Alleyn, Athena Failla, Young Cho, Andrew J. Cooke, Lakshmi Galam, Ramani Soundararajan, Nirmal Sharma, Richard F. Lockey, Narasaiah Kolliputi

Molecular Medicine Faculty Publications

Atp8b1 (ATPase, aminophospholipid transporter, class I, type 8B, member 1) is a cardiolipin transporter in the apical membrane of lung epithelial cells. While the role of Atp8b1 in pneumonia-induced acute lung injury (ALI) has been well studied, its potential role in oxidative stress-induced ALI is poorly understood. We herein show that Atp8b1G308V/G308V mice under hyperoxic conditions display exacerbated cell apoptosis at alveolar epithelium and aberrant proliferation of club cells at bronchiolar epithelium. This hyperoxia-induced ambivalent response in Atp8b1G308V/G308V lungs was followed by patchy distribution of non-uniform interstitial fibrosis at late recovery phase under normoxia. Since this club cell abnormality is …

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Elucidating The Inhibitory Potential Of Designed Peptides Against Amyloid Fibrillation And Amyloid Associated Cytotoxicity, Mohammad K. Siddiqi, Parvez Alam, Tabish Iqbal, Nabeela Majid, Sadia Malik, Saima Nusrat, Aftab Alam, Mohd R. Ajmal, Vladimir N. Uversky, Rizwan H. Khan

Molecular Medicine Faculty Publications

Inhibition of fibrillation process and disaggregation of mature fibrils using small peptide are the promising remedial strategies to combat neurodegenerative diseases. However, designing peptide-based drugs to target β-sheet-rich amyloid has been a major challenge. The current work describes, for the first time, the amyloid inhibitory potential of the two short peptides (selected on the basis of predisposition of their amino acid residues toward β-sheet formation) using combination of biophysical, imaging methods, and docking approaches. Results showed that peptides employed different mechanisms to inhibit the amyloid fibrillation. Furthermore, they were also effective in blocking the amyloid fibrillation pathway. In contrary to …

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Intrinsic Disorder And Posttranslational Modifications: The Darker Side Of The Biological Dark Matter, April L. Darling, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) are functional proteins and domains that devoid stable secondary and/or tertiary structure. IDPs/IDPRs are abundantly present in various proteomes, where they are involved in regulation, signaling, and control, thereby serving as crucial regulators of various cellular processes. Various mechanisms are utilized to tightly regulate and modulate biological functions, structural properties, cellular levels, and localization of these important controllers. Among these regulatory mechanisms are precisely controlled degradation and different posttranslational modifications (PTMs). Many normal cellular processes are associated with the presence of the right amounts of precisely activated IDPs at right …

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Insights Into The Molecular Mechanisms Of Alzheimer’S And Parkinson’S Diseases With Molecular Simulations: Understanding The Roles Of Artificial And Pathological Missense Mutations In Intrinsically Disordered Proteins Related To Pathology, Orkid Coskuner-Weber, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs), which are at the center of Alzheimer’s and Parkinson’s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer’s and Parkinson’s diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics …

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Anti-Correlation Between The Dynamics Of The Active Site Loop And C-Terminal Tail In Relation To The Homodimer Asymmetry Of The Mouse Erythroid 5-Aminolevulinate Synthase, Insung Na, Dominique Catena, Min J. Kong, Gloria C. Ferreira, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Biosynthesis of heme represents a complex process that involves multiple stages controlled by different enzymes. The first of these proteins is a pyridoxal 5′-phosphate (PLP)-dependent homodimeric enzyme, 5-aminolevulinate synthase (ALAS), that catalyzes the rate-limiting step in heme biosynthesis, the condensation of glycine with succinyl-CoA. Genetic mutations in human erythroid-specific ALAS (ALAS2) are associated with two inherited blood disorders, X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP). XLSA is caused by diminished ALAS2 activity leading to decreased ALA and heme syntheses and ultimately ineffective erythropoiesis, whereas XLPP results from “gain-of-function” ALAS2 mutations and consequent overproduction of protoporphyrin IX and increase in …

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Arrestins: Structural Disorder Creates Rich Functionality, Vsevolod V. Gurevich, Eugenia V. Gurevich, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Arrestins are soluble relatively small 44–46 kDa proteins that specifically bind hundreds of active phosphorylated GPCRs and dozens of non-receptor partners. There are binding partners that demonstrate preference for each of the known arrestin conformations: free, receptor-bound, and microtubule-bound. Recent evidence suggests that conformational flexibility in every functional state is the defining characteristic of arrestins. Flexibility, or plasticity, of proteins is often described as structural disorder, in contrast to the fixed conformational order observed in high-resolution crystal structures. However, protein-protein interactions often involve highly flexible elements that can assume many distinct conformations upon binding to different partners. Existing evidence suggests …

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Characterization Of The Virulence Of A Non-Rt027, Non-Rt078 And Binary Toxin-Positive Clostridium Difficile Strain Associated With Severe Diarhea, Chunhui Li, Céline Harmanus, Duolong Zhu, Xiujuan Meng, Shaohui Wang, Juping Duan, Sidi Liu, Chenchao Fu, Pengcheng Zhou, Ruisi Liu, Anhua Wu, Ed J. Kuijper, Wiep Klaas Smits, Lei Fu, Xingmin Sun

Molecular Medicine Faculty Publications

The expression of the Clostridium difficile binary toxin CDT is generally observed in the RT027 (ST1) and RT078 (ST11) C. difficile isolates, which are associated with severe C. difficile infection (CDI). However, we recently reported that the non-RT027 and non-RT078 C. difficile strain LC693 (TcdA+TcdB+ CDT+, ST201) caused severe diarrhea in a patient in Xiangya Hospital in China. C.difficile LC693 is a member of Clade 3, and in this study, we identified LC693 as RT871 and compared its virulence and pathogenicity to those of C.difficile R20291 (TcdA+TcdB+CDT+, ST1/RT027), UK6 (TcdA+TcdB+CDT+, ST35/RT027), CD630 (TcdA+TcdB+CDT−, ST54, RT012), and 1379 (TcdA+TcdB+CDT−, ST54/RT012), with …

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Deciphering The Dark Proteome Of Chikungunya Virus, Ankur Singh, Ankur Kumar, Rakhi Yadav, Vladimir N. Uversky, Rajanish Giri

Molecular Medicine Faculty Publications

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus. The outbreak of CHIKV infection has been seen in many tropical and subtropical regions of the biosphere. Current reports evidenced that after outbreaks in 2005–06, the fitness of this virus propagating in Aedes albopictus enhanced due to the epistatic mutational changes in its envelope protein. In our study, we evaluated the prevalence of intrinsically disordered proteins (IDPs) and IDP regions (IDPRs) in CHIKV proteome. IDPs/IDPRs are known as members of a ‘Dark Proteome’ that defined as a set of polypeptide segments or whole protein without unique three-dimensional structure within the cellular milieu but …

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Full-Text Articles in Medicine and Health Sciences

Molecular Medicine Faculty Publications

Prediction Of Disordered Regions And Their Roles In The Anti-Pathogenic And Immunomodulatory Functions Of Butyrophilins, Elrashdy M. Redwan, Ahmed M. Al-Hejin, Hussein A. Almehdar, Abdulrahman Elsaway, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Molecular Medicine Faculty Publications

Intrinsically Disordered Proteins And The Janus Challenge, Prakash Kulkarni, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Understanding The Interactability Of Chikungunya Virus Proteins Via Molecular Recognition Feature Analysis, Ankur Singh, Ankur Kumar, Vladimir N. Uversky, Rajanish Giri

Molecular Medicine Faculty Publications

Elucidating Feed‑Forward Apoptosis Signatures In Breast Cancer Datasets: Higher Fos Expression Associated With A Better Outcome, Diana A. Fisler, Dhiraj Sikaria, John M. Yavorski, Yaping N. Tu, George Blanck

Molecular Medicine Faculty Publications

Molecular Medicine Faculty Publications

Elucidating The Inhibitory Potential Of Designed Peptides Against Amyloid Fibrillation And Amyloid Associated Cytotoxicity, Mohammad K. Siddiqi, Parvez Alam, Tabish Iqbal, Nabeela Majid, Sadia Malik, Saima Nusrat, Aftab Alam, Mohd R. Ajmal, Vladimir N. Uversky, Rizwan H. Khan

Molecular Medicine Faculty Publications

Intrinsic Disorder And Posttranslational Modifications: The Darker Side Of The Biological Dark Matter, April L. Darling, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Insights Into The Molecular Mechanisms Of Alzheimer’S And Parkinson’S Diseases With Molecular Simulations: Understanding The Roles Of Artificial And Pathological Missense Mutations In Intrinsically Disordered Proteins Related To Pathology, Orkid Coskuner-Weber, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Anti-Correlation Between The Dynamics Of The Active Site Loop And C-Terminal Tail In Relation To The Homodimer Asymmetry Of The Mouse Erythroid 5-Aminolevulinate Synthase, Insung Na, Dominique Catena, Min J. Kong, Gloria C. Ferreira, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Arrestins: Structural Disorder Creates Rich Functionality, Vsevolod V. Gurevich, Eugenia V. Gurevich, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Molecular Medicine Faculty Publications

Deciphering The Dark Proteome Of Chikungunya Virus, Ankur Singh, Ankur Kumar, Rakhi Yadav, Vladimir N. Uversky, Rajanish Giri

Molecular Medicine Faculty Publications