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Articles 1 - 22 of 22
Full-Text Articles in Medicine and Health Sciences
Α-Synuclein Fibrils As Penrose Machines: A Chameleon In The Gear, Francesca De Giorgi, Vladimir N. Uversky, François Ichas
Α-Synuclein Fibrils As Penrose Machines: A Chameleon In The Gear, Francesca De Giorgi, Vladimir N. Uversky, François Ichas
Molecular Medicine Faculty Publications
In 1957, Lionel Penrose built the first man-made self-replicating mechanical device and illustrated its function in a series of machine prototypes, prefiguring our current view of the genesis and the proliferation of amyloid fibrils. He invented and demonstrated, with the help of his son Roger, the concepts that decades later, would become the fundamentals of prion and prion-like neurobiology: nucleation, seeding and conformational templating of monomers, linear polymer elongation, fragmentation, and spread. He published his premonitory discovery in a movie he publicly presented at only two conferences in 1958, a movie we thus reproduce here. By making a 30-year-jump in …
Hepatitis C Virus Infection And Intrinsic Disorder In The Signaling Pathways Induced By Toll-Like Receptors, Elrashdy M. Redwan, Abdullah A. Aljadawi, Vladimir N. Uversky
Hepatitis C Virus Infection And Intrinsic Disorder In The Signaling Pathways Induced By Toll-Like Receptors, Elrashdy M. Redwan, Abdullah A. Aljadawi, Vladimir N. Uversky
Molecular Medicine Faculty Publications
In this study, we examined the interplay between protein intrinsic disorder, hepatitis C virus (HCV) infection, and signaling pathways induced by Toll-like receptors (TLRs). To this end, 10 HCV proteins, 10 human TLRs, and 41 proteins from the TLR-induced downstream pathways were considered from the prevalence of intrinsic disorder. Mapping of the intrinsic disorder to the HCV-TLR interactome and to the TLR-based pathways of human innate immune response to the HCV infection demonstrates that substantial levels of intrinsic disorder are characteristic for proteins involved in the regulation and execution of these innate immunity pathways and in HCV-TLR interaction. Disordered regions, …
Fight Fire With Fire: The Need For A Vaccine Based On Intrinsic Disorder And Structural Flexibility, Vladimir N. Uversky
Fight Fire With Fire: The Need For A Vaccine Based On Intrinsic Disorder And Structural Flexibility, Vladimir N. Uversky
Molecular Medicine Faculty Publications
The absence of advancement in finding efficient vaccines for several human viruses, such as hepatitis C virus (HCV), human immunodeficiency virus type 1 (HIV-1), and herpes simplex viruses (HSVs) despite 30, 40, and even 60 years of research, respectively, is unnerving. Among objective reasons for such failure are the highly glycosylated nature of proteins used as primary vaccine targets against these viruses and the presence of neotopes and cryptotopes, as well as high mutation rates of the RNA viruses HCV and HIV-1 and the capability to establish latency by HSVs. However, the lack of success in utilization of the structure-based …
Intrinsic Disorder As A Natural Preservative: High Levels Of Intrinsic Disorder In Proteins Found In The 2600-Year-Old Human Brain, Aaron S. Mohammed, Vladimir N. Uversky
Intrinsic Disorder As A Natural Preservative: High Levels Of Intrinsic Disorder In Proteins Found In The 2600-Year-Old Human Brain, Aaron S. Mohammed, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Proteomic analysis revealed the preservation of many proteins in the Heslington brain (which is at least 2600-year-old brain tissue uncovered within the skull excavated in 2008 from a pit in Heslington, Yorkshire, England). Five of these proteins—“main proteins”: heavy, medium, and light neurofilament proteins (NFH, NFM, and NFL), glial fibrillary acidic protein (GFAP), and myelin basic (MBP) protein—are engaged in the formation of non-amyloid protein aggregates, such as intermediate filaments and myelin sheath. We used a wide spectrum of bioinformatics tools to evaluate the prevalence of functional disorder in several related sets of proteins, such as the main proteins and …
Editorial: Intrinsically Disordered Proteins And Regions: The Challenge To The Structure-Function Relationship, Angelo Toto, Pietro Sormanni, Cristina Paissoni, Vladimir N. Uversky
Editorial: Intrinsically Disordered Proteins And Regions: The Challenge To The Structure-Function Relationship, Angelo Toto, Pietro Sormanni, Cristina Paissoni, Vladimir N. Uversky
Molecular Medicine Faculty Publications
No abstract provided.
Looking At The Pathogenesis Of The Rabies Lyssavirus Strain Pasteur Vaccins Through A Prism Of The Disorder-Based Bioinformatics, Surya Dhulipala, Vladimir N. Uversky
Looking At The Pathogenesis Of The Rabies Lyssavirus Strain Pasteur Vaccins Through A Prism Of The Disorder-Based Bioinformatics, Surya Dhulipala, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Rabies is a neurological disease that causes between 40,000 and 70,000 deaths every year. Once a rabies patient has become symptomatic, there is no effective treatment for the illness, and in unvaccinated individuals, the case-fatality rate of rabies is close to 100%. French scientists Louis Pasteur and Émile Roux developed the first vaccine for rabies in 1885. If administered before the virus reaches the brain, the modern rabies vaccine imparts long-lasting immunity to the virus and saves more than 250,000 people every year. However, the rabies virus can suppress the host’s immune response once it has entered the cells of …
Theater In The Self-Cleaning Cell: Intrinsically Disordered Proteins Or Protein Regions Acting With Membranes In Autophagy, Hana Popelka, Vladimir N. Uversky
Theater In The Self-Cleaning Cell: Intrinsically Disordered Proteins Or Protein Regions Acting With Membranes In Autophagy, Hana Popelka, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Intrinsically disordered proteins and protein regions (IDPs/IDPRs) are mainly involved in signaling pathways, where fast regulation, temporal interactions, promiscuous interactions, and assemblies of structurally diverse components including membranes are essential. The autophagy pathway builds, de novo, a membrane organelle, the autophagosome, using carefully orchestrated interactions between proteins and lipid bilayers. Here, we discuss molecular mechanisms related to the protein disorder-based interactions of the autophagy machinery with membranes. We describe not only membrane binding phenomenon, but also examples of membrane remodeling processes including membrane tethering, bending, curvature sensing, and/or fragmentation of membrane organelles such as the endoplasmic reticulum, which is an …
Intrinsic Disorder In Tetratricopeptide Repeat Proteins, Nathan W. Bibber, Cornelia Haerle, Roy Khalifa, Bin Xue, Vladimir N. Uversky
Intrinsic Disorder In Tetratricopeptide Repeat Proteins, Nathan W. Bibber, Cornelia Haerle, Roy Khalifa, Bin Xue, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Among the realm of repeat containing proteins that commonly serve as “scaffolds” promoting protein-protein interactions, there is a family of proteins containing between 2 and 20 tetratricopeptide repeats (TPRs), which are functional motifs consisting of 34 amino acids. The most distinguishing feature of TPR domains is their ability to stack continuously one upon the other, with these stacked repeats being able to affect interaction with binding partners either sequentially or in combination. It is known that many repeat-containing proteins are characterized by high levels of intrinsic disorder, and that many protein tandem repeats can be intrinsically disordered. Furthermore, it seems …
The Pathophysiological Significance Of Fibulin-3, Imogen Livingstone, Vladimir N. Uversky, Dominic Furniss, Akira Wiberg
The Pathophysiological Significance Of Fibulin-3, Imogen Livingstone, Vladimir N. Uversky, Dominic Furniss, Akira Wiberg
Molecular Medicine Faculty Publications
Fibulin-3 (also known as EGF-containing fibulin extracellular matrix protein 1 (EFEMP1)) is a secreted extracellular matrix glycoprotein, encoded by the EFEMP1 gene that belongs to the eight-membered fibulin protein family. It has emerged as a functionally unique member of this family, with a diverse array of pathophysiological associations predominantly centered on its role as a modulator of extracellular matrix (ECM) biology. Fibulin-3 is widely expressed in the human body, especially in elastic-fibre-rich tissues and ocular structures, and interacts with enzymatic ECM regulators, including tissue inhibitor of metalloproteinase-3 (TIMP-3). A point mutation in EFEMP1 causes an inherited early-onset form of macular …
Zooming Into The Dark Side Of Human Annexin-S100 Complexes: Dynamic Alliance Of Flexible Partners, Judith Weisz, Vladimir N. Uversky
Zooming Into The Dark Side Of Human Annexin-S100 Complexes: Dynamic Alliance Of Flexible Partners, Judith Weisz, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Annexins and S100 proteins form two large families of Ca2+-binding proteins. They are quite different both structurally and functionally, with S100 proteins being small (10–12 kDa) acidic regulatory proteins from the EF-hand superfamily of Ca2+-binding proteins, and with annexins being at least three-fold larger (329 ± 12 versus 98 ± 7 residues) and using non-EF-hand-based mechanism for calcium binding. Members of both families have multiple biological roles, being able to bind to a large cohort of partners and possessing a multitude of functions. Furthermore, annexins and S100 proteins can interact with each other in either a Ca2+-dependent or Ca2+-independent manner, …
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 …
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 …
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 …
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 …
Intrinsically Disordered Proteins And The Janus Challenge, Prakash Kulkarni, Vladimir N. Uversky
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 …
Intrinsic Disorder In Proteins With Pathogenic Repeat Expansions, April L. Darling, Vladimir N. Uversky
Intrinsic Disorder In Proteins With Pathogenic Repeat Expansions, April L. Darling, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Intrinsically disordered proteins and proteins with intrinsically disordered regions have been shown to be highly prevalent in disease. Furthermore, disease-causing expansions of the regions containing tandem amino acid repeats often push repetitive proteins towards formation of irreversible aggregates. In fact, in disease-relevant proteins, the increased repeat length often positively correlates with the increased aggregation efficiency and the increased disease severity and penetrance, being negatively correlated with the age of disease onset. The major categories of repeat extensions involved in disease include poly-glutamine and poly-alanine homorepeats, which are often times located in the intrinsically disordered regions, as well as repeats in …
Regulation Of Palmitoylation Enzymes And Substrates By Intrinsically Disordered Regions, Krishna D. Reddy
Regulation Of Palmitoylation Enzymes And Substrates By Intrinsically Disordered Regions, Krishna D. Reddy
USF Tampa Graduate Theses and Dissertations
Protein palmitoylation refers to the process of adding a 16-carbon saturated fatty acid to the cysteine of a substrate protein, and this can in turn affect the substrate’s localization, stability, folding, and several other processes. This process is catalyzed by a family of 23 mammalian protein acyltransferases (PATs), a family of transmembrane enzymes that modify an estimated 10% of the proteome. At this point in time, no structure of a protein in this family has been solved, and therefore there is poor understanding about the regulation of the enzymes and their substrates. Most proteins, including palmitoylation enzymes and substrates, have …
The Alphabet Of Intrinsic Disorder: I. Act Like A Pro: On The Abundance And Roles Of Proline Residues In Intrinsically Disordered Proteins, Francois-Xavier Theillet, Lajos Kalmar, Peter Tompa, Kyou-Hoon Han, Philipp Selenko, A. Keith Dunker, Gary W. Daughdrill, Vladimir N. Uversky
The Alphabet Of Intrinsic Disorder: I. Act Like A Pro: On The Abundance And Roles Of Proline Residues In Intrinsically Disordered Proteins, Francois-Xavier Theillet, Lajos Kalmar, Peter Tompa, Kyou-Hoon Han, Philipp Selenko, A. Keith Dunker, Gary W. Daughdrill, Vladimir N. Uversky
Molecular Medicine Faculty Publications
A significant fraction of every proteome is occupied by biologically active proteins that do not form unique three-dimensional structures. These intrinsically disordered proteins (IDPs) and IDP regions (IDPRs) have essential biological functions and are characterized by extensive structural plasticity. Such structural and functional behavior is encoded in the amino acid sequences of IDPs/IDPRs, which are enriched in disorder-promoting residues and depleted in order-promoting residues. In fact, amino acid residues can be arranged according to their disorder-promoting tendency to form an alphabet of intrinsic disorder that defines the structural complexity and diversity of IDPs/IDPRs. This review is the first in a …
The Alphabet Of Intrinsic Disorder: Ii. Various Roles Of Glutamic Acid In Ordered And Intrinsically Disordered Proteins, Vladimir N. Uversky
The Alphabet Of Intrinsic Disorder: Ii. Various Roles Of Glutamic Acid In Ordered And Intrinsically Disordered Proteins, Vladimir N. Uversky
Molecular Medicine Faculty Publications
The ability of a protein to fold into unique functional state or to stay intrinsically disordered is encoded in its amino acid sequence. Both ordered and intrinsically disordered proteins (IDPs) are natural polypeptides that use the same arsenal of 20 proteinogenic amino acid residues as their major building blocks. The exceptional structural plasticity of IDPs, their capability to exist as heterogeneous structural ensembles and their wide array of important disorder-based biological functions that complements functional repertoire of ordered proteins are all rooted within the peculiar differential usage of these building blocks by ordered proteins and IDPs. In fact, some residues …
Biophysical Characterization Of Α-Synuclein And Rotenone Interaction, Blanca A. Silva, Olöf Einarsdóttir, Anthony L. Fink, Vladimir N. Uversky
Biophysical Characterization Of Α-Synuclein And Rotenone Interaction, Blanca A. Silva, Olöf Einarsdóttir, Anthony L. Fink, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Previous studies revealed that pesticides interact with α-synuclein and accelerate the rate of fibrillation. These results are consistent with the prevailing hypothesis that the direct interaction of α-synuclein with pesticides is one of many suspected factors leading to α-synuclein fibrillation and ultimately to Parkinson's disease. In this study, the biophysical properties and fibrillation kinetics of α-synuclein in the presence of rotenone were investigated and, more specifically, the effects of rotenone on the early-stage misfolded forms of α-synuclein were considered. The thioflavine T (ThT) fluorescence assay studies provide evidence that early-phase misfolded α-synuclein forms are affected by rotenone and that the …
Modulating Α-Synuclein Misfolding And Fibrillation In Vitro By Agrochemicals, Blanca A. Silva, Olöf Einarsdóttir, Anthony L. Fink, Vladimir N. Uversky
Modulating Α-Synuclein Misfolding And Fibrillation In Vitro By Agrochemicals, Blanca A. Silva, Olöf Einarsdóttir, Anthony L. Fink, Vladimir N. Uversky
Molecular Medicine Faculty Publications
A combination of spectroscopic techniques including atomic force microscopy (AFM) and transmission electron microscopy (TEM), was used to analyze the effect of chemically distinct agrochemicals (pesticides, herbicides, and fungicides) on the in vitro misfolding and aggregation of a presynaptic intrinsically disordered protein α-synuclein. Despite their differences in chemical properties, almost all the compounds screened affected the α-synuclein fibrillation in a concentration-dependent manner. The morphology of the aggregated α-synuclein was characterized by AFM and TEM techniques. In addition to typical fibrils abundantly found at the equilibrium phase, this analysis revealed the existence of a noticeable nonfibrillar fraction where α-synuclein was present …
Calbindin-D28k Acts As A Calcium-Dependent Chaperone Suppressing Α-Synuclein Fibrillation In Vitro, Wenbo Zhou, Chunmei Long, Anthony L. Fink, Vladimir N. Uversky
Calbindin-D28k Acts As A Calcium-Dependent Chaperone Suppressing Α-Synuclein Fibrillation In Vitro, Wenbo Zhou, Chunmei Long, Anthony L. Fink, Vladimir N. Uversky
Molecular Medicine Faculty Publications
α-Synuclein, a natively unfolded protein aggregation which is implicated in the pathogenesis of Parkinson’s disease and several other neurodegenerative diseases, is known to interact with a great number of unrelated proteins. Some of these proteins, such as ß-synuclein and DJ-1, were shown to inhibit α-synuclein aggregation in vitro and in vivo therefore acting as chaperones. Since calbindin-D28K is co-localized with Ca2+ neuronal membrane pumps, and since α-synuclein is also found in the membrane proximity, these two proteins can potentially interact in vivo. Here we show that calbindin-D28K interacts with α-synuclein and inhibits its fibrillation in a calcium-dependent manner, therefore potentially …