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Articles 1 - 21 of 21
Full-Text Articles in Entire DC Network
Intrinsic Disorder-Based Emergence In Cellular Biology: Physiological And Pathological Liquid-Liquid Phase Transitions In Cells, April L. Darling, Boris Zaslavsky, Vladimir N. Uversky
Intrinsic Disorder-Based Emergence In Cellular Biology: Physiological And Pathological Liquid-Liquid Phase Transitions In Cells, April L. Darling, Boris Zaslavsky, Vladimir N. Uversky
Molecular Medicine Faculty Publications
The visible outcome of liquid-liquid phase transitions (LLPTs) in cells is the formation and disintegration of various proteinaceous membrane-less organelles (PMLOs). Although LLPTs and related PMLOs have been observed in living cells for over 200 years, the physiological functions of these transitions (also known as liquid-liquid phase separation, LLPS) are just starting to be understood. While unveiling the functionality of these transitions is important, they have come into light more recently due to the association of abnormal LLPTs with various pathological conditions. In fact, several maladies, such as various cancers, different neurodegenerative diseases, and cardiovascular diseases, are known to be …
Evolutionary Analyses Of Sequence And Structure Space Unravel The Structural Facets Of Sod1, Sourav Chowdury, Dwipanjan Sanyal, Sagnik Sen, Vladimir N. Uversky, Ujjwal Maulik, Krishnananda Chattopadhyay
Evolutionary Analyses Of Sequence And Structure Space Unravel The Structural Facets Of Sod1, Sourav Chowdury, Dwipanjan Sanyal, Sagnik Sen, Vladimir N. Uversky, Ujjwal Maulik, Krishnananda Chattopadhyay
Molecular Medicine Faculty Publications
Superoxide dismutase (SOD) is the primary enzyme of the cellular antioxidant defense cascade. Misfolding, concomitant oligomerization, and higher order aggregation of human cytosolic SOD are linked to amyotrophic lateral sclerosis (ALS). Although, with two metal ion cofactors SOD1 is extremely robust, the de-metallated apo form is intrinsically disordered. Since the rise of oxygen-based metabolism and antioxidant defense systems are evolutionary coupled, SOD is an interesting protein with a deep evolutionary history. We deployed statistical analysis of sequence space to decode evolutionarily co-varying residues in this protein. These were validated by applying graph theoretical modelling to understand the impact of the …
Driving Forces Of Liquid–Liquid Phase Separation In Biological Systems, Boris Y. Zaslavsky, Luisa A. Ferreira, Vladimir N. Uversky
Driving Forces Of Liquid–Liquid Phase Separation In Biological Systems, Boris Y. Zaslavsky, Luisa A. Ferreira, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Analysis of liquid–liquid phase separation in biological systems shows that this process is similar to the phase separation observed in aqueous two-phase systems formed by nonionic polymers, proteins, and polysaccharides. The emergence of interfacial tension is a necessary condition of phase separation. The situation in this regard is similar to that of phase separation in mixtures of partially miscible solvents. It is suggested that the evaluation of the effects of biological macromolecules on the solvent properties of aqueous media and the measurement of the interfacial tension as a function of these solvent properties may be more productive for gaining insights …
Zika And Flavivirus Shell Disorder: Virulence And Fetal Morbidity, Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster, Vladimir N. Uversky
Zika And Flavivirus Shell Disorder: Virulence And Fetal Morbidity, Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Zika virus (ZIKV) was first discovered in 1947 in Africa. Since then, sporadic ZIKV infections of humans have been reported in Africa and Asia. For a long time, this virus was mostly unnoticed due to its mild symptoms and low fatality rates. However, during the 2015–2016 epidemic in Central and South America, when millions of people were infected, it was discovered that ZIKV causes microcephaly in the babies of mothers infected during pregnancy. An examination of the M and C proteins of the ZIKV shell using the disorder predictor PONDR VLXT revealed that the M protein contains relatively high disorder …
Supramolecular Fuzziness Of Intracellular Liquid Droplets: Liquid–Liquid Phase Transitions, Membrane-Less Organelles, And Intrinsic Disorder, Vladimir N. Uversky
Supramolecular Fuzziness Of Intracellular Liquid Droplets: Liquid–Liquid Phase Transitions, Membrane-Less Organelles, And Intrinsic Disorder, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Cells are inhomogeneously crowded, possessing a wide range of intracellular liquid droplets abundantly present in the cytoplasm of eukaryotic and bacterial cells, in the mitochondrial matrix and nucleoplasm of eukaryotes, and in the chloroplast’s stroma of plant cells. These proteinaceous membrane-less organelles (PMLOs) not only represent a natural method of intracellular compartmentalization, which is crucial for successful execution of various biological functions, but also serve as important means for the processing of local information and rapid response to the fluctuations in environmental conditions. Since PMLOs, being complex macromolecular assemblages, possess many characteristic features of liquids, they represent highly dynamic (or …
Rational Discovery Of Antimetastatic Agents Targeting The Intrinsically Disordered Region Of Mbd2, Min Young Kim, Insung Na, Ji Sook Kim, Seung Han Son, Sungwoo Choi, Seol Eui Lee, Ji-Hun Kim, Kiseok Jang, Gil Alterovitz, Yu Chen, Arjant Van Der Vaar, Hyung-Sik Won, Vladimir N. Uversky, Chul Geun Kim
Rational Discovery Of Antimetastatic Agents Targeting The Intrinsically Disordered Region Of Mbd2, Min Young Kim, Insung Na, Ji Sook Kim, Seung Han Son, Sungwoo Choi, Seol Eui Lee, Ji-Hun Kim, Kiseok Jang, Gil Alterovitz, Yu Chen, Arjant Van Der Vaar, Hyung-Sik Won, Vladimir N. Uversky, Chul Geun Kim
Molecular Medicine Faculty Publications
Although intrinsically disordered protein regions (IDPRs) are commonly engaged in promiscuous protein-protein interactions (PPIs), using them as drug targets is challenging due to their extreme structural flexibility. We report a rational discovery of inhibitors targeting an IDPR of MBD2 that undergoes disorder-to-order transition upon PPI and is critical for the regulation of the Mi-2/NuRD chromatin remodeling complex (CRC). Computational biology was essential for identifying target site, searching for promising leads, and assessing their binding feasibility and off-target probability. Molecular action of selected leads inhibiting the targeted PPI of MBD2 was validated in vitro and in cell, followed by confirming their …
Experimental Insight Into The Structural And Functional Roles Of The ‘Black’ And ‘Gray’ Clusters In Recoverin, A Calcium Binding Protein With Four Ef-Hand Motifs, Sergei E. Permyakov, Alisa S. Vologzhannikova, Ekaterina L. Nemashkalova, Alexei S. Kazakov, Alexander I. Denesyuk, Konstantin Denessiouk, Viktoriia E. Baksheeva, Andrey A. Zamyatnin Jr., Eugene Yu. Zernii, Vladimir N. Uversky, Eugene A. Permyakov
Experimental Insight Into The Structural And Functional Roles Of The ‘Black’ And ‘Gray’ Clusters In Recoverin, A Calcium Binding Protein With Four Ef-Hand Motifs, Sergei E. Permyakov, Alisa S. Vologzhannikova, Ekaterina L. Nemashkalova, Alexei S. Kazakov, Alexander I. Denesyuk, Konstantin Denessiouk, Viktoriia E. Baksheeva, Andrey A. Zamyatnin Jr., Eugene Yu. Zernii, Vladimir N. Uversky, Eugene A. Permyakov
Molecular Medicine Faculty Publications
Recently, we have found that calcium binding proteins of the EF-hand superfamily (i.e., a large family of proteins containing helix-loop-helix calcium binding motif or EF-hand) contain two types of conserved clusters called cluster I (‘black’ cluster) and cluster II (‘grey’ cluster), which provide a supporting scaffold for the Ca2+ binding loops and contribute to the hydrophobic core of the EF-hand domains. Cluster I is more conservative and mostly incorporates aromatic amino acids, whereas cluster II includes a mix of aromatic, hydrophobic, and polar amino acids of different sizes. Recoverin is EF-hand Ca2+-binding protein containing two ‘black’ clusters comprised of F35, …
Intrinsic Disorder Of The Baf Complex: Roles In Chromatin Remodeling And Disease Development, Nashwa El Hadidy, Vladimir N. Uversky
Intrinsic Disorder Of The Baf Complex: Roles In Chromatin Remodeling And Disease Development, Nashwa El Hadidy, Vladimir N. Uversky
Molecular Medicine Faculty Publications
The two-meter-long DNA is compressed into chromatin in the nucleus of every cell, which serves as a significant barrier to transcription. Therefore, for processes such as replication and transcription to occur, the highly compacted chromatin must be relaxed, and the processes required for chromatin reorganization for the aim of replication or transcription are controlled by ATP-dependent nucleosome remodelers. One of the most highly studied remodelers of this kind is the BRG1- or BRM-associated factor complex (BAF complex, also known as SWItch/sucrose non-fermentable (SWI/SNF) complex), which is crucial for the regulation of gene expression and differentiation in eukaryotes. Chromatin remodeling complex …
Many-To-One Binding By Intrinsically Disordered Protein Regions, Wei-Lun Alterovitz, Eshel Faraggi, Christopher J. Oldfield, Jingwei Meng, Bin Xue, Fei Huang, Pedro Romero, Andrzej Kloczkowski, Vladimir N. Uversky, A. Keith Dunker
Many-To-One Binding By Intrinsically Disordered Protein Regions, Wei-Lun Alterovitz, Eshel Faraggi, Christopher J. Oldfield, Jingwei Meng, Bin Xue, Fei Huang, Pedro Romero, Andrzej Kloczkowski, Vladimir N. Uversky, A. Keith Dunker
Molecular Medicine Faculty Publications
Disordered binding regions (DBRs), which are embedded within intrinsically disordered proteins or regions (IDPs or IDRs), enable IDPs or IDRs to mediate multiple protein-protein interactions. DBR-protein complexes were collected from the Protein Data Bank for which two or more DBRs having different amino acid sequences bind to the same (100% sequence identical) globular protein partner, a type of interaction herein called many-to-one binding. Two distinct binding profiles were identified: independent and overlapping. For the overlapping binding profiles, the distinct DBRs interact by means of almost identical binding sites (herein called “similar”), or the binding sites contain both common and divergent …
Intrinsically Disordered Proteins In Chronic Diseases, Prakash Kulkarni, Vladimir N. Uversky
Intrinsically Disordered Proteins In Chronic Diseases, Prakash Kulkarni, Vladimir N. Uversky
Molecular Medicine Faculty Publications
No abstract provided.
Hiv Vaccine Mystery And Viral Shell Disorder, Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster, Vladimir N. Uversky
Hiv Vaccine Mystery And Viral Shell Disorder, Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Hundreds of billions of dollars have been spent for over three decades in the search for an effective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two other sexually transmitted viruses, for which no vaccine is available, the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Traditional textbook explanatory paradigm of rapid mutation of retroviruses cannot adequately address the unavailability of vaccine for many sexually transmissible viruses, since HSV and HCV are DNA and non-retroviral RNA viruses, respectively, whereas effective vaccine for the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV), …
On The Need To Develop Guidelines For Characterizing And Reporting Intrinsic Disorder In Proteins, Michael Vincent, Vladimir N. Uversky, Santiago Schnell
On The Need To Develop Guidelines For Characterizing And Reporting Intrinsic Disorder In Proteins, Michael Vincent, Vladimir N. Uversky, Santiago Schnell
Molecular Medicine Faculty Publications
Since the early 2000s, numerous computational tools have been created and used to predict intrinsic disorder in proteins. At present, the output from these algorithms is difficult to interpret in the absence of standards or references for comparison. There are many reasons to establish a set of standard-based guidelines to evaluate computational protein disorder predictions. This viewpoint explores a handful of these reasons, including standardizing nomenclature to improve communication, rigor and reproducibility, and making it easier for newcomers to enter the field. An approach for reporting predicted disorder in single proteins with respect to whole proteomes is discussed. The suggestions …
Ifi16, A Nuclear Innate Immune Dna Sensor, Mediates Epigenetic Silencing Of Herpesvirus Genomes By Its Association With H3k9 Methyltransferases Suv39h1 And Glp, Arunava Roy, Anandita Ghosh, Binod Kumar, Bala Chandran
Ifi16, A Nuclear Innate Immune Dna Sensor, Mediates Epigenetic Silencing Of Herpesvirus Genomes By Its Association With H3k9 Methyltransferases Suv39h1 And Glp, Arunava Roy, Anandita Ghosh, Binod Kumar, Bala Chandran
Molecular Medicine Faculty Publications
IFI16, an innate immune DNA sensor, recognizes the nuclear episomal herpes viral genomes and induces the inflammasome and interferon-β responses. IFI16 also regulates cellular transcription and act as a DNA virus restriction factor. IFI16 knockdown disrupted the latency of Kaposi’s sarcoma associated herpesvirus (KSHV) and induced lytic transcripts. However, the mechanism of IFI16’s transcription regulation is unknown. Here, we show that IFI16 is in complex with the H3K9 methyltransferase SUV39H1 and GLP and recruits them to the KSHV genome during de novo infection and latency. The resulting depositions of H3K9me2/me3 serve as a docking site for the heterochromatin-inducing HP1α protein …
Cyclized Ndga Modifies Dynamic Α-Synuclein Monomers Preventing Aggregation And Toxicity, Malcolm J. Daniels, J. Brucker Nourse, Hanna Kim, Valerio Sainati, Marco Schiavina, Maria Grazia Murrali, Buyan Pan, John J. Ferrie, Conor M. Haney, Rani Moons, Neal S. Gould, Antonino Natalello, Rita Grandori, Frank Sobott, E. James Petersson, Elizabeth Rhoades, Roberta Pierattelli, Isabella Felli, Vladimir N. Uversky, Kim A. Caldwell, Guy A. Caldwell, Edward S. Krol, Harry Ischiropoulos
Cyclized Ndga Modifies Dynamic Α-Synuclein Monomers Preventing Aggregation And Toxicity, Malcolm J. Daniels, J. Brucker Nourse, Hanna Kim, Valerio Sainati, Marco Schiavina, Maria Grazia Murrali, Buyan Pan, John J. Ferrie, Conor M. Haney, Rani Moons, Neal S. Gould, Antonino Natalello, Rita Grandori, Frank Sobott, E. James Petersson, Elizabeth Rhoades, Roberta Pierattelli, Isabella Felli, Vladimir N. Uversky, Kim A. Caldwell, Guy A. Caldwell, Edward S. Krol, Harry Ischiropoulos
Molecular Medicine Faculty Publications
Growing evidence implicates α-synuclein aggregation as a key driver of neurodegeneration in Parkinson’s disease (PD) and other neurodegenerative disorders. Herein, the molecular and structural mechanisms of inhibiting α-synuclein aggregation by novel analogs of nordihydroguaiaretic acid (NDGA), a phenolic dibenzenediol lignan, were explored using an array of biochemical and biophysical methodologies. NDGA analogs induced modest, progressive compaction of monomeric α-synuclein, preventing aggregation into amyloid-like fibrils. This conformational remodeling preserved the dynamic adoption of α-helical conformations, which are essential for physiological membrane interactions. Oxidation-dependent NDGA cyclization was required for the interaction with monomeric α-synuclein. NDGA analog-pretreated α-synuclein did not aggregate even without …
Intrinsically Disordered Proteins And Their “Mysterious” (Meta)Physics, Vladimir N. Uversky
Intrinsically Disordered Proteins And Their “Mysterious” (Meta)Physics, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Recognition of the natural abundance and functional importance of intrinsically disordered proteins (IDPs), and protein hybrids that contain both intrinsically disordered protein regions (IDPRs) and ordered regions, is changing protein science. IDPs and IDPRs, i.e., functional proteins and protein regions without unique structures, can often be found in all organisms, and typically play vital roles in various biological processes. Disorder-based functionality complements the functions of ordered proteins and domains. However, by virtue of their existence, IDPs/IDPRs, which are characterized by remarkable conformational flexibility and structural plasticity, break multiple rules established over the years to explain structure, folding, and functionality of …
Small Heat Shock Proteins, Big Impact On Protein Aggregation In Neurodegenerative Disease, Jack M. Webster, April L. Darling, Vladimir N. Uversky, Laura J. Blair
Small Heat Shock Proteins, Big Impact On Protein Aggregation In Neurodegenerative Disease, Jack M. Webster, April L. Darling, Vladimir N. Uversky, Laura J. Blair
Molecular Medicine Faculty Publications
Misfolding, aggregation, and aberrant accumulation of proteins are central components in the progression of neurodegenerative disease. Cellular molecular chaperone systems modulate proteostasis, and, therefore, are primed to influence aberrant protein-induced neurotoxicity and disease progression. Molecular chaperones have a wide range of functions from facilitating proper nascent folding and refolding to degradation or sequestration of misfolded substrates. In disease states, molecular chaperones can display protective or aberrant effects, including the promotion and stabilization of toxic protein aggregates. This seems to be dependent on the aggregating protein and discrete chaperone interaction. Small heat shock proteins (sHsps) are a class of molecular chaperones …
Life In Phases: Intra- And Inter- Molecular Phase Transitions In Protein Solutions, Vladimir N. Uversky, Alexey V. Finkelstein
Life In Phases: Intra- And Inter- Molecular Phase Transitions In Protein Solutions, Vladimir N. Uversky, Alexey V. Finkelstein
Molecular Medicine Faculty Publications
Proteins, these evolutionarily-edited biological polymers, are able to undergo intramolecular and intermolecular phase transitions. Spontaneous intramolecular phase transitions define the folding of globular proteins, whereas binding-induced, intra- and inter- molecular phase transitions play a crucial role in the functionality of many intrinsically-disordered proteins. On the other hand, intermolecular phase transitions are the behind-the-scenes players in a diverse set of macrosystemic phenomena taking place in protein solutions, such as new phase nucleation in bulk, on the interface, and on the impurities, protein crystallization, protein aggregation, the formation of amyloid fibrils, and intermolecular liquid–liquid or liquid–gel phase transitions associated with the biogenesis …
Bioinformatics Haracterisation Of The (Mutated) Proteins Related To Andersen–Tawil Syndrome, Carlos Polanco, Vladimir N. Uversky, Manlio F. Márquez, Thomas Buhse, Miguel Arias Estrada, Alberto Huberman
Bioinformatics Haracterisation Of The (Mutated) Proteins Related To Andersen–Tawil Syndrome, Carlos Polanco, Vladimir N. Uversky, Manlio F. Márquez, Thomas Buhse, Miguel Arias Estrada, Alberto Huberman
Molecular Medicine Faculty Publications
In the last two decades, a group of proteins whose mutations are associated with a disease manifested by episodes of muscle weakness (periodic paralysis), changes in heart rhythm (arrhythmia), and developmental abnormalities has been under constant study. This malady is known as Andersen–Tawil syndrome, with ~60% of cases of this syndrome being caused by 16 mutations in the KCNJ2 gene [UniProt ID: P63252-01—P63252-17]. In this work, we present a computational study designed to obtain a fingerprint of Andersen–Tawil mutated proteins and differentiate them from mutated proteins associated with Brugada syndrome and from functional groups of proteins belonging to APD3, UniProt, …
Development Of A Mel Cell-Derived Allograft Mouse Model For Cancer Research, Min Young Kim, Sungwoo Choi, Seol Eui Lee, Ji Sook Kim, Seung Han Son, Young Soo Lim, Bang-Jin Kim, Buom-Yong Ryu, Vladimir N. Uversky, Young Jin Lee, Chul Geun Kim
Development Of A Mel Cell-Derived Allograft Mouse Model For Cancer Research, Min Young Kim, Sungwoo Choi, Seol Eui Lee, Ji Sook Kim, Seung Han Son, Young Soo Lim, Bang-Jin Kim, Buom-Yong Ryu, Vladimir N. Uversky, Young Jin Lee, Chul Geun Kim
Molecular Medicine Faculty Publications
Murine erythroleukemia (MEL) cells are often employed as a model to dissect mechanisms of erythropoiesis and erythroleukemia in vitro. Here, an allograft model using MEL cells resulting in splenomegaly was established to develop a diagnostic model for isolation/quantification of metastatic cells, anti-cancer drug screening, and evaluation of the tumorigenic or metastatic potentials of molecules in vivo. In this animal model, circulating MEL cells from the blood stream were successfully isolated and quantified with an additional in vitro cultivation step. In terms of the molecular-pathological analysis, we were able to successfully evaluate the functional discrimination between methyl-CpG-binding domain 2 (Mbd2) and …
Structural And Dynamical Order Of A Disordered Protein: Molecular Insights Into Conformational Switching Of Page4 At The Systems Level, Xingcheng Lin, Prakash Kulkarni, Federico Bocci, Nicholas P. Schafer, Susmita Roy, Min-Yeh Tsai, Yanan He, Yihong Chen, Krithika Rajagopalan, Steven M. Mooney, Yu Zeng, Keith Weninger, Alex Grishaev, José N. Onuchic, Herbet Levine, Peter G. Wolynes, Ravi Salgia, Govindan Rangarajan, Vladimir N. Uversky, John Orban, Mohit Kumar Jolly
Structural And Dynamical Order Of A Disordered Protein: Molecular Insights Into Conformational Switching Of Page4 At The Systems Level, Xingcheng Lin, Prakash Kulkarni, Federico Bocci, Nicholas P. Schafer, Susmita Roy, Min-Yeh Tsai, Yanan He, Yihong Chen, Krithika Rajagopalan, Steven M. Mooney, Yu Zeng, Keith Weninger, Alex Grishaev, José N. Onuchic, Herbet Levine, Peter G. Wolynes, Ravi Salgia, Govindan Rangarajan, Vladimir N. Uversky, John Orban, Mohit Kumar Jolly
Molecular Medicine Faculty Publications
Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions. Many IDPs undergo function-related disorder-to-order transitions driven by their interaction with specific binding partners. As experimental techniques become more sensitive and become better integrated with computational simulations, we are beginning to see how the modest structural ordering …
Structure Determination By Single-Particle Cryo-Electron Microscopy: Only The Sky (And Intrinsic Disorder) Is The Limit, Emeka Nwanochie, Vladimir N. Uversky
Structure Determination By Single-Particle Cryo-Electron Microscopy: Only The Sky (And Intrinsic Disorder) Is The Limit, Emeka Nwanochie, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Traditionally, X-ray crystallography and NMR spectroscopy represent major workhorses of structural biologists, with the lion share of protein structures reported in protein data bank (PDB) being generated by these powerful techniques. Despite their wide utilization in protein structure determination, these two techniques have logical limitations, with X-ray crystallography being unsuitable for the analysis of highly dynamic structures and with NMR spectroscopy being restricted to the analysis of relatively small proteins. In recent years, we have witnessed an explosive development of the techniques based on Cryo-electron microscopy (Cryo-EM) for structural characterization of biological molecules. In fact, single-particle Cryo-EM is a special …