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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.
Liaisons Dangereuses: Intrinsic Disorder In Cellular Proteins Recruited To Viral Infection-Related Biocondensates, Greta Bianchi, Stefania Brocca, Sonia Longhi, Vladimir N. Uversky
Liaisons Dangereuses: Intrinsic Disorder In Cellular Proteins Recruited To Viral Infection-Related Biocondensates, Greta Bianchi, Stefania Brocca, Sonia Longhi, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Liquid–liquid phase separation (LLPS) is responsible for the formation of so-called membrane-less organelles (MLOs) that are essential for the spatio-temporal organization of the cell. Intrinsically disordered proteins (IDPs) or regions (IDRs), either alone or in conjunction with nucleic acids, are involved in the formation of these intracellular condensates. Notably, viruses exploit LLPS at their own benefit to form viral replication compartments. Beyond giving rise to biomolecular condensates, viral proteins are also known to partition into cellular MLOs, thus raising the question as to whether these cellular phase-separating proteins are drivers of LLPS or behave as clients/regulators. Here, we focus on …
Biapss: A Comprehensive Physicochemical Analyzer Of Proteins Undergoing Liquid–Liquid Phase Separation, Aleksandra E. Badaczewska-Dawid, Vladimir N. Uversky, Davit A. Potoyan
Biapss: A Comprehensive Physicochemical Analyzer Of Proteins Undergoing Liquid–Liquid Phase Separation, Aleksandra E. Badaczewska-Dawid, Vladimir N. Uversky, Davit A. Potoyan
Molecular Medicine Faculty Publications
The liquid–liquid phase separation (LLPS) of biomolecules is a phenomenon which is nowadays recognized as the driving force for the biogenesis of numerous functional membraneless organelles and cellular bodies. The interplay between the protein primary sequence and phase separation remains poorly understood, despite intensive research. To uncover the sequence-encoded signals of protein capable of undergoing LLPS, we developed a novel web platform named BIAPSS (Bioinformatics Analysis of LLPS Sequences). This web server provides on-the-fly analysis, visualization, and interpretation of the physicochemical and structural features for the superset of curated LLPS proteins.
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 …
Structural Protein Analysis Of Driver Gene Mutations In Conjunctival Melanoma, Mak B. Djulbegovic, Vladimir N. Uversky, J. William Harbour, Anat Galor, Carol L. Karp
Structural Protein Analysis Of Driver Gene Mutations In Conjunctival Melanoma, Mak B. Djulbegovic, Vladimir N. Uversky, J. William Harbour, Anat Galor, Carol L. Karp
Molecular Medicine Faculty Publications
In recent years, there has been tremendous enthusiasm with respect to detailing the genetic basis of many neoplasms, including conjunctival melanoma (CM). We aim to analyze five proteins associated with CM, namely BRAF, NRAS, c-KIT, NF1, and PTEN. We evaluated each protein for its intrinsically disordered protein regions (IDPRs) and its protein-protein interactions (PPI) with the Predictor of Natural Disordered Protein Regions (PONDR®) and the Search Tool for the Retrieval of Interacting Genes (STRING®). Our PONDR® analysis found high levels of IDPRs in all five proteins with mutations linked to CM. The highest levels of IDPRs were in BRAF (45.95%), …
Liquid–Liquid Phase Separation By Intrinsically Disordered Protein Regions Of Viruses: Roles In Viral Life Cycle And Control Of Virus–Host Interactions, Stefania Brocca, Rita Grandori, Sonia Longhi, Vladimir N. Uversky
Liquid–Liquid Phase Separation By Intrinsically Disordered Protein Regions Of Viruses: Roles In Viral Life Cycle And Control Of Virus–Host Interactions, Stefania Brocca, Rita Grandori, Sonia Longhi, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Intrinsically disordered proteins (IDPs) are unable to adopt a unique 3D structure under physiological conditions and thus exist as highly dynamic conformational ensembles. IDPs are ubiquitous and widely spread in the protein realm. In the last decade, compelling experimental evidence has been gathered, pointing to the ability of IDPs and intrinsically disordered regions (IDRs) to undergo liquid–liquid phase separation (LLPS), a phenomenon driving the formation of membrane-less organelles (MLOs). These biological condensates play a critical role in the spatio-temporal organization of the cell, where they exert a multitude of key biological functions, ranging from transcriptional regulation and silencing to control …
Unstructured Biology Of Proteins From Ubiquitin-Proteasome System: Roles In Cancer And Neurodegenerative Diseases, Kundlik Gadhave, Prateek Kumar, Shivani K. Kapuganti, Vladimir N. Uversky, Rajanish Giri
Unstructured Biology Of Proteins From Ubiquitin-Proteasome System: Roles In Cancer And Neurodegenerative Diseases, Kundlik Gadhave, Prateek Kumar, Shivani K. Kapuganti, Vladimir N. Uversky, Rajanish Giri
Molecular Medicine Faculty Publications
The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure–function relationships of UPS components have not been identified completely; therefore, in this study, we have …
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 …
A Comprehensive Survey Of The Roles Of Highly Disordered Proteins In Type 2 Diabetes, Zhihua Du, Vladimir N. Uversky
A Comprehensive Survey Of The Roles Of Highly Disordered Proteins In Type 2 Diabetes, Zhihua Du, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that is strongly associated with hyperglycemia (high blood sugar) related to either insulin resistance or insufficient insulin production. Among the various molecular events and players implicated in the manifestation and development of diabetes mellitus, proteins play several important roles. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database has information on 34 human proteins experimentally shown to be related to the T2DM pathogenesis. It is known that many proteins associated with different human maladies are intrinsically disordered as a whole, or contain intrinsically disordered regions. The presented study shows …
An Intrinsically Disordered Region Of The Acetyltransferase P300 With Similarity To Prion-Like Domains Plays A Role In Aggregation, Alexander Kirilyuk, Mika Shimoji, Jason Catania, Geetaram Sahu, Nagarajan Pattabiraman, Antonio Giordano, Christopher Albanese, Italo Mocchetti, Jeffrey A. Toretsky, Vladimir N. Uversky, Maria Laura Avantaggiati
An Intrinsically Disordered Region Of The Acetyltransferase P300 With Similarity To Prion-Like Domains Plays A Role In Aggregation, Alexander Kirilyuk, Mika Shimoji, Jason Catania, Geetaram Sahu, Nagarajan Pattabiraman, Antonio Giordano, Christopher Albanese, Italo Mocchetti, Jeffrey A. Toretsky, Vladimir N. Uversky, Maria Laura Avantaggiati
Molecular Medicine Faculty Publications
Several human diseases including neurodegenerative disorders and cancer are associated with abnormal accumulation and aggregation of misfolded proteins. Proteins with high tendency to aggregate include the p53 gene product, TAU and alpha synuclein. The potential toxicity of aberrantly folded proteins is limited via their transport into intracellular sub-compartments, the aggresomes, where misfolded proteins are stored or cleared via autophagy. We have identified a region of the acetyltransferase p300 that is highly disordered and displays similarities with prion-like domains. We show that this region is encoded as an alternative spliced variant independently of the acetyltransferase domain, and provides an interaction interface …
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 …
Malleable Machines In Transcription Regulation: The Mediator Complex, Ágnes Tóth-Petróczy, Christopher J. Oldfield, István Simon, Yuichiro Takagi, A. Keith Dunker, Vladimir N. Uversky, Monika Fuxreiter
Malleable Machines In Transcription Regulation: The Mediator Complex, Ágnes Tóth-Petróczy, Christopher J. Oldfield, István Simon, Yuichiro Takagi, A. Keith Dunker, Vladimir N. Uversky, Monika Fuxreiter
Molecular Medicine Faculty Publications
The Mediator complex provides an interface between gene-specific regulatory proteins and the general transcription machinery including RNA polymerase II (RNAP II). The complex has a modular architecture (Head, Middle, and Tail) and cryoelectron microscopy analysis suggested that it undergoes dramatic conformational changes upon interactions with activators and RNAP II. These rearrangements have been proposed to play a role in the assembly of the preinitiation complex and also to contribute to the regulatory mechanism of Mediator. In analogy to many regulatory and transcriptional proteins, we reasoned that Mediator might also utilize intrinsically disordered regions (IDRs) to facilitate structural transitions and transmit …