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https://www.readbyqxmd.com/read/29453740/arrestins-structural-disorder-creates-rich-functionality
#1
REVIEW
Vsevolod V Gurevich, Eugenia V Gurevich, Vladimir N Uversky
Arrestins are soluble relatively small 44-46 kDa proteins that specifically bind hundreds of active phosphorylated GPCRs and dozens of non-receptor partners. There are binding partners that demonstrate preference for each of the known arrestin conformations: free, receptor-bound, and microtubule-bound. Recent evidence suggests that conformational flexibility in every functional state is the defining characteristic of arrestins. Flexibility, or plasticity, of proteins is often described as structural disorder, in contrast to the fixed conformational order observed in high-resolution crystal structures...
February 16, 2018: Protein & Cell
https://www.readbyqxmd.com/read/29452354/alpha-synuclein-inhibits-snx3-retromer-mediated-retrograde-recycling-of-iron-transporters-in-s-cerevisiae-and-c-elegans-models-of-parkinson-s-disease
#2
Dhaval Patel, Chuan Xu, Sureshbabu Nagarajan, Zhengchang Liu, Wayne O Hemphill, Runhua Shi, Vladimir N Uversky, Guy A Caldwell, Kim A Caldwell, Stephan N Witt
We probed the role of alpha-synuclein (α-syn) in modulating sorting nexin 3 (Snx3)-retromer-mediated recycling of iron transporters in Saccharomyces cerevisiae and Caenorhabditis elegans. In yeast, the membrane-bound heterodimer Fet3/Ftr1 is the high affinity iron importer. Fet3 is a membrane-bound multicopper ferroxidase, whose ferroxidase domain is orthologous to human ceruloplasmin (Cp), that oxidizes external Fe+2 to Fe+3; the Fe+3 ions then channel through the Ftr1 permease into the cell. When the concentration of external iron is low (< 1 µM), Fet3/Ftr1 is maintained on the plasma membrane by retrograde endocytic-recycling; whereas, when the concentration of external iron is high (> 10 µM), Fet3/Ftr1 is endocytosed and shunted to the vacuole for degradation...
February 14, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29414700/structural-impact-of-phosphorylation-and-dielectric-constant-variation-on-synaptotagmin-s-idr
#3
Michael E Fealey, Benjamin P Binder, Vladimir N Uversky, Anne Hinderliter, David D Thomas
We used time-resolved Förster resonance energy transfer, circular dichroism, and molecular dynamics simulation to investigate the structural dependence of synaptotagmin 1's intrinsically disordered region (IDR) on phosphorylation and dielectric constant. We found that a peptide corresponding to the full-length IDR sequence, a ∼60-residue strong polyampholyte, can sample structurally collapsed states in aqueous solution, consistent with its κ-predicted behavior, where κ is a sequence-dependent parameter that is used to predict IDR compaction...
February 6, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29413001/intrinsic-disorder-protein-protein-interactions-and-disease
#4
Vladimir N Uversky
It is recognized now that biologically active proteins without stable tertiary structure (known as intrinsically disordered proteins, IDPs) and hybrid proteins containing ordered domains and intrinsically disordered protein regions (IDPRs) are important players found in any given proteome. These IDPs/IDPRs possess functions that complement functional repertoire of their ordered counterparts, being commonly related to recognition, as well as control and regulation of various signaling pathways. They are interaction masters, being able to utilize a wide spectrum of interaction mechanisms, ranging from induced folding to formation of fuzzy complexes where significant levels of disorder are preserved, to polyvalent stochastic interactions playing crucial roles in the liquid-liquid phase transitions leading to the formation of proteinaceous membrane-less organelles...
2018: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/29401697/prediction-of-disordered-regions-and-their-roles-in-the-anti-pathogenic-and-immunomodulatory-functions-of-butyrophilins
#5
Elrashdy M Redwan, Ahmed M Al-Hejin, Hussein A Almehdar, Abdelrahman M Elsaway, Vladimir N Uversky
Butyrophilins (BTNs) are a group of the moonlighting proteins, some members of which are secreted in milk. They constitute a large family of structurally similar type 1 transmembrane proteins from the immunoglobulin superfamily. Although the founding member of this family is related to lactation, participating in the secretion, formation and stabilization of milk fat globules, it may also have a cell surface receptor function. Generally, the BTN family members are known to modulate co-stimulatory responses, T cell selection, differentiation, and cell fate determination...
February 4, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29364151/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
#6
REVIEW
Orkid Coskuner-Weber, Vladimir N Uversky
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...
January 24, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29303563/in-aqua-veritas-indispensable-yet-mostly-ignored-role-of-water-in-phase-separation-and-membrane-less-organelles
#7
Boris Y Zaslavsky, Vladimir N Uversky
Despite a common practice of presenting structures of biological molecules on empty background and assumption that interactions between biological macromolecules take place within the inert solvent, water represents an active component of various biological processes. This perspective addresses indispensable, yet mostly ignored, roles of water in biological liquid-liquid phase transitions and in the biogenesis of various proteinaceous membrane-less organelles. It is pointed out that changes in the water structure reflected in the changes of its abilities to donate and/or accept hydrogen bond and participate in dipole-dipole and dipole-induced dipole interactions in the presence of various solutes (ranging from small molecules, to synthetic polymers, and to biological macromolecules) might represent a driving force of the liquid-liquid phase separation, define partition of various solutes in formed phases, and define the exceptional ability of intrinsically disordered proteins to be engaged in the formation of proteinaceous membrane-less organelles...
January 5, 2018: Biochemistry
https://www.readbyqxmd.com/read/29237329/not-all-amlets-are-made-equal-complexes-of-cow-and-camel-%C3%AE-lactalbumin-with-oleic-acid-show-different-structure-and-stability
#8
Leonid Breydo, Hussein A Almehdar, Esmail M El-Fakharany, Elrashdy M Redwan, Vladimir N Uversky
No abstract text is available yet for this article.
December 13, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29218307/calreticulin-challenges-posed-by-the-intrinsically-disordered-nature-of-calreticulin-to-the-study-of-its-function
#9
Lilian Varricchio, Mario Falchi, Massimiliano Dall'Ora, Caterina De Benedittis, Alessandra Ruggeri, Vladimir N Uversky, Anna Rita Migliaccio
Calreticulin is a Ca2+-binding chaperone protein, which resides mainly in the endoplasmic reticulum but also found in other cellular compartments including the plasma membrane. In addition to Ca2+, calreticulin binds and regulates almost all proteins and most of the mRNAs deciding their intracellular fate. The potential functions of calreticulin are so numerous that identification of all of them is becoming a nightmare. Still the recent discovery that patients affected by the Philadelphia-negative myeloproliferative disorders essential thrombocytemia or primary myelofibrosis not harboring JAK2 mutations carry instead calreticulin mutations disrupting its C-terminal domain has highlighted the clinical need to gain a deeper understanding of the biological activity of this protein...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/29183267/in-silico-evaluation-of-the-resistance-of-the-t790m-variant-of-epidermal-growth-factor-receptor-kinase-to-cancer-drug-erlotinib
#10
Inderpal Singh, Shashank Singh, Vijeshwar Verma, Vladimir N Uversky, Ratna Chandra
Epidermal growth factor receptor (EGFR) kinase is implicated in cancer development due to either overexpression or activation variants in its functional intracellular kinase domain. Threonine to Methionine (Thr 790 Met) is one such variant observed commonly in patients showing resistance to kinase inhibitor drug Erlotinib. Two mechanisms for resistance have been proposed (1) steric hindrance and (2) enhanced binding to ATP. In this study, we employed molecular dynamics simulations and studied both the mechanisms...
November 28, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29165363/identification-and-initial-characterization-of-the-effectors-of-an-anther-smut-fungus-and-potential-host-target-proteins
#11
Venkata S Kuppireddy, Vladimir N Uversky, Su San Toh, Ming-Chang Tsai, William C Beckerson, Catarina Cahill, Brittany Carman, Michael H Perlin
(1) Background: Plant pathogenic fungi often display high levels of host specificity and biotrophic fungi; in particular, they must manipulate their hosts to avoid detection and to complete their obligate pathogenic lifecycles. One important strategy of such fungi is the secretion of small proteins that serve as effectors in this process. Microbotryum violaceum is a species complex whose members infect members of the Caryophyllaceae; M. lychnidis-dioicae, a parasite on Silene latifolia, is one of the best studied interactions...
November 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29080786/molecular-recognition-features-in-zika-virus-proteome
#12
Pushpendra Mani Mishra, Vladimir N Uversky, Rajanish Giri
Viruses have compact genomes that encode limited number of proteins in comparison to other biological entities. Interestingly, viral proteins have shown natural abundance of either completely disordered proteins that are recognized as intrinsically disorder proteins (IDPs) or partially disordered segments known as intrinsically disordered protein regions (IDPRs). IDPRs are involved in interactions with multiple binding partners to accomplish signaling, regulation, and control functions in cells. Tuning of IDPs and IDPRs are mediated through post-translational modification and alternative splicing...
October 25, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29068531/intrinsically-disordered-proteome-of-human-membrane-less-organelles
#13
REVIEW
April Darling, Yun Liu, Christopher J Oldfield, Vladimir N Uversky
It is recognized now that various proteinaceous membrane-less organelles (PMLOs) are commonly found in cytoplasm, nucleus, and mitochondria of various eukaryotic cells (as well as in the chloroplasts of plant cells). Being different from the "traditional" membrane-encapsulated organelles, such as chloroplasts, endoplasmic reticulum, Golgi apparatus, lysosomes, mitochondria, nucleus, and vacuoles, PMLOs solve the cellular need to facilitate and regulate molecular interactions via reversible and controllable isolation of target molecules in specialized compartments...
October 25, 2017: Proteomics
https://www.readbyqxmd.com/read/29029791/in-search-for-globally-disordered-apo-parvalbumins-case-of-parvalbumin-%C3%AE-1-from-coho-salmon
#14
Alisa A Vologzhannikova, Polina A Khorn, Alexei S Kazakov, Ramis G Ismailov, Andrei S Sokolov, Vladimir N Uversky, Eugene A Permyakov, Sergei E Permyakov
Parvalbumin (PA) is a classical EF-hand calcium-binding protein of muscle, neuronal, and other tissues, and a major fish allergen. Although certain apo-PAs lack tertiary structure, functional implications of that feature and its structural prerequisites remain unclear. In a search for unstable PAs, we probed conformational stability of parvalbumin β-1 from coho salmon (csPA), a cold water fish species, using circular dichroism, scanning calorimetry, hydrophobic probe fluorescence, limited proteolysis, chemical crosslinking and dynamic light scattering techniques...
November 2017: Cell Calcium
https://www.readbyqxmd.com/read/29018861/role-of-solvent-properties-of-water-in-crowding-effects-induced-by-macromolecular-agents-and-osmolytes
#15
L A Ferreira, V N Uversky, B Y Zaslavsky
Solvent properties of water in aqueous solutions of polyethylene glycols of various molecular weights, l-proline, betaine, and a series of chlorides of varied concentrations are assayed using three solvatochromic dyes. The properties include solvent dipolarity/polarizability, hydrogen bond donor acidity, and hydrogen bond acceptor basicity. These properties are also evaluated in mixtures of two polymers, polymer and osmolyte, and two osmolytes. It is shown that linear combinations of solvent dipolarity/polarizability and hydrogen bond donor acidity assayed in individual solutions of crowders strongly correlate with the effects of the crowders on the stability of various proteins and nucleic acids reported in the literature...
November 21, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28980860/the-roles-of-intrinsic-disorder-based-liquid-liquid-phase-transitions-in-the-dr-jekyll-mr-hyde-behavior-of-proteins-involved-in-amyotrophic-lateral-sclerosis-and-frontotemporal-lobar-degeneration
#16
Vladimir N Uversky
Pathological developments leading to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are associated with misbehavior of several key proteins, such as SOD1 (superoxide dismutase 1), TARDBP/TDP-43, FUS, C9orf72, and dipeptide repeat proteins generated as a result of the translation of the intronic hexanucleotide expansions in the C9orf72 gene, PFN1 (profilin 1), GLE1 (GLE1, RNA export mediator), PURA (purine rich element binding protein A), FLCN (folliculin), RBM45 (RNA binding motif protein 45), SS18L1/CREST, HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), ATXN2 (ataxin 2), MAPT (microtubule associated protein tau), and TIA1 (TIA1 cytotoxic granule associated RNA binding protein)...
October 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28971739/potential-functions-of-lea-proteins-from-the-brine-shrimp-artemia-franciscana-anhydrobiosis-meets-bioinformatics
#17
Brett Janis, Vladimir N Uversky, Michael A Menze
Late embryogenesis abundant (LEA) proteins are a large group of anhydrobiosis-associated intrinsically disordered proteins (IDP), which are commonly found in plants and some animals. The brine shrimp Artemiafranciscana is the only known animal that expresses LEA proteins from three, and not only one, different groups in its anhydrobiotic life stage. The reason for the higher complexity in the A. franciscana LEA proteome (LEAome), compared with other anhydrobiotic animals, remains mostly unknown. To address this issue, we have employed a suite of bioinformatics tools to evaluate the disorder status of the ArtemiaLEAome and to analyze the roles of intrinsic disorder in functioning of brine shrimp LEA proteins...
October 3, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28949782/divergent-anticancer-activity-of-free-and-formulated-camel-milk-%C3%AE-lactalbumin
#18
COMPARATIVE STUDY
Vladimir N Uversky, Esmail M El-Fakharany, Marwa M Abu-Serie, Hussein A Almehdar, Elrashdy M Redwan
Alpha-lactalbumin (α-LA), a small milk calcium-binding globular protein, is known to possess noticeable anticancer activity, which is determined by the ability of this protein to form complexes with oleic acid (OA). To date, in addition to human and bovine α-LA, the ability to form such anti-tumor complexes with OA was described for goat and camel α-LA. Although the mechanisms of the anticancer activity of human and bovine α-LA are already well-studied, little is currently known about the anticancer action of this camel protein...
October 21, 2017: Cancer Investigation
https://www.readbyqxmd.com/read/28934129/a-comprehensive-survey-of-the-roles-of-highly-disordered-proteins-in-type-2-diabetes
#19
Zhihua Du, Vladimir N Uversky
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...
September 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28925982/osmolyte-like-stabilizing-effects-of-low-gdnhcl-concentrations-on-d-glucose-d-galactose-binding-protein
#20
Alexander V Fonin, Alexandra D Golikova, Irina A Zvereva, Sabato D'Auria, Maria Staiano, Vladimir N Uversky, Irina M Kuznetsova, Konstantin K Turoverov
The ability of d-glucose/d-galactose-binding protein (GGBP) to reversibly interact with its ligands, glucose and galactose, makes this protein an attractive candidate for sensing elements of glucose biosensors. This potential is largely responsible for attracting researchers to study the conformational properties of this protein. Previously, we showed that an increase in the fluorescence intensity of the fluorescent dye 6-bromoacetyl-2-dimetylaminonaphtalene (BADAN) is linked to the holo-form of the GGBP/H152C mutant in solutions containing sub-denaturing concentrations of guanidine hydrochloride (GdnHCl)...
September 19, 2017: International Journal of Molecular Sciences
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