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Full-Text Articles in Medicine and Health Sciences
Pre-Molten, Wet, And Dry Molten Globules En Route To The Functional State Of Proteins, Munishwar Nath Gupta, Vladimir N. Uversky
Pre-Molten, Wet, And Dry Molten Globules En Route To The Functional State Of Proteins, Munishwar Nath Gupta, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Transitions between the unfolded and native states of the ordered globular proteins are accompanied by the accumulation of several intermediates, such as pre-molten globules, wet molten globules, and dry molten globules. Structurally equivalent conformations can serve as native functional states of intrinsically disordered proteins. This overview captures the characteristics and importance of these molten globules in both structured and intrinsically disordered proteins. It also discusses examples of engineered molten globules. The formation of these intermediates under conditions of macromolecular crowding and their interactions with nanomaterials are also reviewed.
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.
On The Roles Of Intrinsically Disordered Proteins And Regions In Cell Communication And Signaling, Sarah E. Bondos, A. Keith Dunker, Vladimir N. Uversky
On The Roles Of Intrinsically Disordered Proteins And Regions In Cell Communication And Signaling, Sarah E. Bondos, A. Keith Dunker, Vladimir N. Uversky
Molecular Medicine Faculty Publications
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 …
Disphscan: A Multi-Sequence Web Tool For Predicting Protein Disorder As A Function Of Ph, Carlos Pintado-Grima, Valentín Iglesias, Jaime Santos, Vladimir N. Uversky, Salvador Ventura
Disphscan: A Multi-Sequence Web Tool For Predicting Protein Disorder As A Function Of Ph, Carlos Pintado-Grima, Valentín Iglesias, Jaime Santos, Vladimir N. Uversky, Salvador Ventura
Molecular Medicine Faculty Publications
Proteins are exposed to fluctuating environmental conditions in their cellular context and during their biotechnological production. Disordered regions are susceptible to these fluctuations and may experience solvent-dependent conformational switches that affect their local dynamism and activity. In a recent study, we modeled the influence of pH in the conformational state of IDPs by exploiting a charge–hydrophobicity diagram that considered the effect of solution pH on both variables. However, it was not possible to predict context-dependent transitions for multiple sequences, precluding proteome-wide analysis or the screening of collections of mutants. In this article, we present DispHScan, the first computational tool dedicated …
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 …
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 …
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 …
Disease-Associated Mutations Disrupt Functionally Important Regions Of Intrinsic Protein Disorder, Vladimir Vacic, Phineus R. L. Markwick, Christopher J. Oldfield, Xiaoyue Zhao, Chad Haynes, Vladimir N. Uversky, Lilia M. Iakoucheva
Disease-Associated Mutations Disrupt Functionally Important Regions Of Intrinsic Protein Disorder, Vladimir Vacic, Phineus R. L. Markwick, Christopher J. Oldfield, Xiaoyue Zhao, Chad Haynes, Vladimir N. Uversky, Lilia M. Iakoucheva
Molecular Medicine Faculty Publications
The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs) and regions (IDRs) in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations …
Free Cysteine Modulates The Conformation Of Human C/Ebp Homologous Protein, Vinay K. Singh, Mona M. Rahman, Kim Munro, Vladimir N. Uversky, Steven P. Smith, Zongchao Jia
Free Cysteine Modulates The Conformation Of Human C/Ebp Homologous Protein, Vinay K. Singh, Mona M. Rahman, Kim Munro, Vladimir N. Uversky, Steven P. Smith, Zongchao Jia
Molecular Medicine Faculty Publications
The C/EBP Homologous Protein (CHOP) is a nuclear protein that is integral to the unfolded protein response culminating from endoplasmic reticulum stress. Previously, CHOP was shown to comprise extensive disordered regions and to self-associate in solution. In the current study, the intrinsically disordered nature of this protein was characterized further by comprehensive in silico analyses. Using circular dichroism, differential scanning calorimetry and nuclear magnetic resonance, we investigated the global conformation and secondary structure of CHOP and demonstrated, for the first time, that conformational changes in this protein can be induced by the free amino acid l-cysteine. Addition of l-cysteine caused …
Influence Of Sequence Changes And Environment On Intrinsically Disordered Proteins, Amrita Mohan, Vladimir N. Uversky, Predrag Radivojac
Influence Of Sequence Changes And Environment On Intrinsically Disordered Proteins, Amrita Mohan, Vladimir N. Uversky, Predrag Radivojac
Molecular Medicine Faculty Publications
Many large-scale studies on intrinsically disordered proteins are implicitly based on the structural models deposited in the Protein Data Bank. Yet, the static nature of deposited models supplies little insight into variation of protein structure and function under diverse cellular and environmental conditions. While the computational predictability of disordered regions provides practical evidence that disorder is an intrinsic property of proteins, the robustness of disordered regions to changes in sequence or environmental conditions has not been systematically studied. We analyzed intrinsically disordered regions in the same or similar proteins crystallized independently and studied their sensitivity to changes in protein sequence …
Intrinsic Disorder Is A Common Feature Of Hub Proteins From Four Eukaryotic Interactomes, Chad Haynes, Christopher J. Oldfield, Fei Ji, Niels Klitgord, Michael E. Cusick, Predrag Radivojac, Vladimir N. Uversky, Mark Vidal, Lilia M. Iakoucheva
Intrinsic Disorder Is A Common Feature Of Hub Proteins From Four Eukaryotic Interactomes, Chad Haynes, Christopher J. Oldfield, Fei Ji, Niels Klitgord, Michael E. Cusick, Predrag Radivojac, Vladimir N. Uversky, Mark Vidal, Lilia M. Iakoucheva
Molecular Medicine Faculty Publications
Recent proteome-wide screening approaches have provided a wealth of information about interacting proteins in various organisms. To test for a potential association between protein connectivity and the amount of predicted structural disorder, the disorder propensities of proteins with various numbers of interacting partners from four eukaryotic organisms (Caenorhabditis elegans, Saccharomyces cerevisiae, Drosophila melanogaster, and Homo sapiens) were investigated. The results of PONDR VL-XT disorder analysis show that for all four studied organisms, hub proteins, defined here as those that interact with ≥10 partners, are significantly more disordered than end proteins, defined here as those that interact with just one partner. …