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Articles 1 - 12 of 12
Full-Text Articles in Medicine and Health Sciences
Granulins Modulate Liquid–Liquid Phase Separation And Aggregation Of The Prion-Like C-Terminal Domain Of The Neurodegeneration-Associated Protein Tdp-43, Anukool A. Bhopatkar, Vladimir N. Uversky, Vijayaraghavan Rangachari
Granulins Modulate Liquid–Liquid Phase Separation And Aggregation Of The Prion-Like C-Terminal Domain Of The Neurodegeneration-Associated Protein Tdp-43, Anukool A. Bhopatkar, Vladimir N. Uversky, Vijayaraghavan Rangachari
Molecular Medicine Faculty Publications
TAR DNA-binding protein 43 (TDP-43) has emerged as a key player in many neurodegenerative pathologies, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Hallmarks of both FTLD and ALS are the toxic cytoplasmic inclusions of the prion-like C-terminal fragments of TDP-43 CTD (TDP-43 C-terminal domain), formed upon proteolytic cleavage of full-length TDP-43 in the nucleus and subsequent transport to the cytoplasm. Both full-length TDP-43 and its CTD are also known to form stress granules by coacervating with RNA in the cytoplasm during stress and may be involved in these pathologies. Furthermore, mutations in the PGRN gene, leading to …
New Technologies To Analyse Protein Function: An Intrinsic Disorder Perspective, Vladimir N. Uversky
New Technologies To Analyse Protein Function: An Intrinsic Disorder Perspective, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Functions of intrinsically disordered proteins do not require structure. Such structure-independent functionality has melted away the classic rigid “lock and key” representation of structure–function relationships in proteins, opening a new page in protein science, where molten keys operate on melted locks and where conformational flexibility and intrinsic disorder, structural plasticity and extreme malleability, multifunctionality and binding promiscuity represent a new-fangled reality. Analysis and understanding of this new reality require novel tools, and some of the techniques elaborated for the examination of intrinsically disordered protein functions are outlined in this review.
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
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 …
Intrinsic Disorder Where You Least Expect It: The Incidence And Functional Relevance Of Intrinsic Disorder In Enzymes And The Protein Data Bank, Shelly Deforte
Intrinsic Disorder Where You Least Expect It: The Incidence And Functional Relevance Of Intrinsic Disorder In Enzymes And The Protein Data Bank, Shelly Deforte
USF Tampa Graduate Theses and Dissertations
Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) exist as interconverting conformational ensembles, without a single fixed three-dimensional structure in vivo. The focus in the literature up to this point has been primarily on IDPs that are mostly or entirely disordered. Therefore, we have an incomplete understanding of the incidence and functional relevance of IDPRs in proteins that have regions of both order and disorder. This work explores these populations, by examining IDPRs in the Protein Data Bank (PDB) and in enzymes. By applying disorder prediction methods combined with an analysis of missing regions in crystal structure data, …
Compartmentalization And Functionality Of Nuclear Disorder: Intrinsic Disorder And Protein-Protein Interactions In Intra-Nuclear Compartments, Fanchi Meng, Insung Na, Lukasz Kurgan, Vladimir N. Uversky
Compartmentalization And Functionality Of Nuclear Disorder: Intrinsic Disorder And Protein-Protein Interactions In Intra-Nuclear Compartments, Fanchi Meng, Insung Na, Lukasz Kurgan, Vladimir N. Uversky
Molecular Medicine Faculty Publications
The cell nucleus contains a number of membrane-less organelles or intra-nuclear compartments. These compartments are dynamic structures representing liquid-droplet phases which are only slightly denser than the bulk intra-nuclear fluid. They possess different functions, have diverse morphologies, and are typically composed of RNA (or, in some cases, DNA) and proteins. We analyzed 3005 mouse proteins localized in specific intra-nuclear organelles, such as nucleolus, chromatin, Cajal bodies, nuclear speckles, promyelocytic leukemia (PML) nuclear bodies, nuclear lamina, nuclear pores, and perinuclear compartment and compared them with ~29,863 non-nuclear proteins from mouse proteome. Our analysis revealed that intrinsic disorder is enriched in the …
Dancing Protein Clouds: The Strange Biology And Chaotic Physics Of Intrinsically Disordered Proteins, Vladimir N. Uversky
Dancing Protein Clouds: The Strange Biology And Chaotic Physics Of Intrinsically Disordered Proteins, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Biologically active but floppy proteins represent a new reality of modern protein science. These intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered and intrinsically disordered protein regions (IDPRs) constitute a noticeable part of any given proteome. Functionally, they complement ordered proteins, and their conformational flexibility and structural plasticity allow them to perform impossible tricks and be engaged in biological activities that are inaccessible to well folded proteins with their unique structures. The major goals of this minireview are to show that, despite their simplified amino acid sequences, IDPs/IDPRs are complex entities often resembling chaotic systems, are structurally and functionally …
Intrinsically Disordered Caldesmon Binds Calmodulin Via The “Buttons On A String” Mechanism, Sergei E. Permyakov, Eugene A. Permyakov, Vladimir N. Uversky
Intrinsically Disordered Caldesmon Binds Calmodulin Via The “Buttons On A String” Mechanism, Sergei E. Permyakov, Eugene A. Permyakov, Vladimir N. Uversky
Molecular Medicine Faculty Publications
We show here that chicken gizzard caldesmon (CaD) and its C-terminal domain (residues 636–771, CaD136) are intrinsically disordered proteins. The computational and experimental analyses of the wild type CaD136 and series of its single tryptophan mutants (W674A, W707A, and W737A) and a double tryptophan mutant (W674A/W707A) suggested that although the interaction of CaD136 with calmodulin (CaM) can be driven by the non-specific electrostatic attraction between these oppositely charged molecules, the specificity of CaD136-CaM binding is likely to be determined by the specific packing of important CaD136 tryptophan residues at the CaD136-CaM interface. It is suggested that this interaction can be …
Intrinsic Disorder In Biomarkers Of Insulin Resistance, Hypoadiponectinemia, And Endothelial Dysfunction Among The Type 2 Diabetic Patients, Osama H. Jiffri, Fadwa M. Al-Sharif, Essam H. Jiffri, Vladimir N. Uversky
Intrinsic Disorder In Biomarkers Of Insulin Resistance, Hypoadiponectinemia, And Endothelial Dysfunction Among The Type 2 Diabetic Patients, Osama H. Jiffri, Fadwa M. Al-Sharif, Essam H. Jiffri, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that is strongly associated with the all-cause and cardiovascular mortality. The present study aimed to analyze the abundance and functionality of intrinsically disordered regions in several biomarkers of insulin resistance, adiponectin, and endothelial dysfunction found in the T2DM patients. In fact, in comparison to controls, obese T2DM patients are known to have significantly higher levels of inter-cellular adhesion molecule (iCAM-1), vascular cell adhesion molecule (vCAM-1), and E-selectin, whereas their adiponectin levels are relatively low. Bioinformatics analysis revealed that these selected biomarkers (iCAM-1, vCAM-1, E-selectin, and adiponectin) are characterized by …
Intrinsic Disorder In Biomarkers Of Insulin Resistance, Hypoadiponectinemia, And Endothelial Dysfunction Among The Type 2 Diabetic Patients, Osama H. Jiffri, Fadwa M. Al-Sharif, Essam H. Jiffri, Vladimir N. Uversky
Intrinsic Disorder In Biomarkers Of Insulin Resistance, Hypoadiponectinemia, And Endothelial Dysfunction Among The Type 2 Diabetic Patients, Osama H. Jiffri, Fadwa M. Al-Sharif, Essam H. Jiffri, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that is strongly associated with the all-cause and cardiovascular mortality. The present study aimed to analyze the abundance and functionality of intrinsically disordered regions in several biomarkers of insulin resistance, adiponectin, and endothelial dysfunction found in the T2DM patients. In fact, in comparison to controls, obese T2DM patients are known to have significantly higher levels of inter-cellular adhesion molecule (iCAM-1), vascular cell adhesion molecule (vCAM-1), and E-selectin, whereas their adiponectin levels are relatively low. Bioinformatics analysis revealed that these selected biomarkers (iCAM-1, vCAM-1, E-selectin, and adiponectin) are characterized by …
Does Intrinsically Disordered Caldesmon Bind Calmodulin Via The “Buttons On A String” Mechanism?, Sergei E. Permyakov, Eugene A. Permyakov, Vladimir N. Uversky
Does Intrinsically Disordered Caldesmon Bind Calmodulin Via The “Buttons On A String” Mechanism?, Sergei E. Permyakov, Eugene A. Permyakov, Vladimir N. Uversky
Molecular Medicine Faculty Publications
We show here that chicken gizzard caldesmon (CaD) and its C-terminal domain (residues 636-771, CaD136) are intrinsically disordered proteins. The computational and experimental analyses of the wild type CaD136 and series of its single tryptophan mutants (W674A, W707A, and W737A) and a double tryptophan mutant (W674A/W707A) suggested that although the interaction of CaD136 with calmodulin (CaM) can be driven by the non-specific electrostatic attraction between these oppositely charged molecules, the specificity of CaD136-CaM binding is likely to be determined by the specific packing of important CaD136 tryptophan residues at the CaD136-CaM interface. It is suggested that this interaction can be …
Does Intrinsically Disordered Caldesmon Bind Calmodulin Via The “Buttons On A String” Mechanism?, Sergei E. Permyakov, Eugene A. Permyakov, Vladimir N. Uversky
Does Intrinsically Disordered Caldesmon Bind Calmodulin Via The “Buttons On A String” Mechanism?, Sergei E. Permyakov, Eugene A. Permyakov, Vladimir N. Uversky
Molecular Medicine Faculty Publications
We show here that chicken gizzard caldesmon (CaD) and its C-terminal domain (residues 636-771, CaD136) are intrinsically disordered proteins. The computational and experimental analyses of the wild type CaD136 and series of its single tryptophan mutants (W674A, W707A, and W737A) and a double tryptophan mutant (W674A/W707A) suggested that although the interaction of CaD136 with calmodulin (CaM) can be driven by the non-specific electrostatic attraction between these oppositely charged molecules, the specificity of CaD136-CaM binding is likely to be determined by the specific packing of important CaD136 tryptophan residues at the CaD136-CaM interface. It is suggested that this interaction can be …
Malleable Ribonucleoprotein Machine: Protein Intrinsic Disorder In The Saccharomyces Cerevisiae Spliceosome, Maria De Lourdes Coelho Ribeiro, Julio Espinosa, Sameen Islam, Osvaldo Martinez, Jayesh Jamnadas Thanki, Stephanie Mazariegos, Tam Nguyen, Maya Larina, Bin Xue, Vladimir N. Uversky
Malleable Ribonucleoprotein Machine: Protein Intrinsic Disorder In The Saccharomyces Cerevisiae Spliceosome, Maria De Lourdes Coelho Ribeiro, Julio Espinosa, Sameen Islam, Osvaldo Martinez, Jayesh Jamnadas Thanki, Stephanie Mazariegos, Tam Nguyen, Maya Larina, Bin Xue, Vladimir N. Uversky
Molecular Medicine Faculty Publications
Recent studies revealed that a significant fraction of any given proteome is presented by proteins that do not have unique 3D structures as a whole or in significant parts. These intrinsically disordered proteins possess dramatic structural and functional variability, being especially enriched in signaling and regulatory functions since their lack of fixed structure defines their ability to be involved in interaction with several proteins and allows them to be re-used in multiple pathways. Among recognized disorder-based protein functions are interactions with nucleic acids and multi-target binding; i.e., the functions ascribed to many spliceosomal proteins. Therefore, the spliceosome, a multimegadalton ribonucleoprotein …