Browsing by Author "Uversky, Vladimir"

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    A Database for Nuclear Receptor DNA Binding Sites
    (2009-11-05T21:54:52Z) Breen, Timothy E.; Uversky, Vladimir
    A database has been developed for nuclear receptor DNA binding sites and the corresponding nuclear receptor DNA binding domain (DBD) amino acid sequences. This database contains three main tables nuclear receptor DNA footprints, nuclear receptor DNA binding sites and the corresponding nuclear receptor DBD. The ultimate goal of this database is to provide a repository for all experimentally derived nuclear receptor DNA binding sites. Finite DNA binding sites and footprints are obtained from original peer reviewed research that used selected experimental methods to identify nuclear receptor DNA binding sites. Acceptable methods for the identification of DNA binding sites and/or footprints include reporter genes and DNA deletion analysis, DNAase I footprinting, exonuclease III footprinting, methylation protection, methylation interference, nuclear receptor protein mutagenesis and the electrophoretic mobility shift assay. With respect to this database, a nuclear receptor footprint is a DNA sequence less than 50 nucleotides in length identified by one of the methods listed above. A binding site is a DNA sequence identified within one of the footprints that is less than 15 nucleotides in length and corresponds to a previously identified half site, response element or consensus sequence. The five prime and three prime location of each footprint with respect to the transcription initiation site is noted in the database. The corresponding nuclear receptor DBD amino acid sequence is obtained from the Swiss-Prot database. The nuclear receptor data is annotated with the literature reference, DNA source, DNA binding site identification method, the nuclear receptor Swiss-Prot primary accession number, and inter halfsite spacing if specified. The tables are related by the literature reference, DNA source, experimental method and nuclear receptor ID. Sixty one publications have been identified from 1983 through 1994 that contain nuclear receptor binding sequences identified with one of the methods listed above. These publications were identified by selected review articles, cited references, citation index and PubMed searches. Currently, the database contains 21 DNA binding sites and 30 DNA footprints from 14 publications between 1983 and 1987. As the database expands, the literature citations will be used to design new search strategies for the nuclear receptor literature. After the current literature has been surveyed and the database is up to date, submissions will be accepted from past and future research. This database will eventually become publicly accessible. In order to interpret the experimentally derived DNA footprints, the specific DNA base - NR protein interactions are summarized from six X ray crystallographic studies.
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    Expression and localization of RGS9-2/G 5/R7BP complex in vivo is set by dynamic control of its constitutive degradation by cellular cysteine proteases
    (Society for Neuroscience, 2007-12-19) Anderson, Garret R.; Lujan, Rafael; Semenov, Arthur; Pravetoni, Marco; Posokhova, Ekaterina N.; Song, Joseph H.; Uversky, Vladimir; Chen, Ching-Kang; Wickman, Kevin; Martemyanov, Kirill A.; Biochemistry and Molecular Biology, School of Medicine
    A member of regulator of G-protein signaling family, RGS9-2, is an essential modulator of signaling through neuronal dopamine and opioid G-protein-coupled receptors. Recent findings indicate that the abundance of RGS9-2 determines sensitivity of signaling in the locomotor and reward systems in the striatum. In this study we report the mechanism that sets the concentration of RGS9-2 in vivo, thus controlling G-protein signaling sensitivity in the region. We found that RGS9-2 possesses specific degradation determinants which target it for constitutive destruction by lysosomal cysteine proteases. Shielding of these determinants by the binding partner R7 binding-protein (R7BP) controls RGS9-2 expression at the posttranslational level. In addition, binding to R7BP in neurons targets RGS9-2 to the specific intracellular compartment, the postsynaptic density. Implementation of this mechanism throughout ontogenetic development ensures expression of RGS9-2/type 5 G-protein beta subunit/R7BP complexes at postsynaptic sites in unison with increased signaling demands at mature synapses.
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    A Novel Strategy for the Development of Vaccines for SARS-CoV-2 (COVID-19) and Other Viruses Using AI and Viral Shell Disorder
    (2020-05-07) Goh, Gerard; Dunker, A. Keith; Foster, James; Uversky, Vladimir; Biochemistry and Molecular Biology, School of Medicine
    A model that predicts levels of coronavirus (CoV) respiratory/fecal-oral transmission potentials based on the outer shell hardness has been built using neural network (artificial intelligence, AI) analysis of the percentage of disorder (PID) in the nucleocapsid, N, and membrane, M, proteins of the inner and outer viral shells, respectively. Based mainly on the PID of N, SARS-CoV-2 is categorized as having intermediate levels of both respiratory and fecal oral transmission potential. Related to this, other studies have found strong positive correlations between virulence and inner shell disorder among numerous viruses, including Nipah, Ebola, and Dengue viruses. There is some evidence that this is also true for SARS-CoV-2 and SARS-CoV, which have N PIDs of 48% and 50%, and are characterized by case-fatality rates of 7.1% and 10.9%, respectively. The link between levels of respiratory transmission and virulence lies in viral load of body fluids and organ respectively. A virus can be infectious via respiratory modes only if the viral loads in saliva and mucus exceed certain minima. Likewise, a person may die, if the viral load is too high especially in viral organs. Inner shell proteins of viruses play important roles in the replication of viruses, and structural disorder enhances these roles by providing greater efficiency in protein-protein/DNA/RNA/lipid binding. This paper outlines a novel strategy in attenuating viruses involving comparison of disorder patterns of inner shells of related viruses to identify residues and regions that could be ideal for mutation. The M protein of SARS-CoV-2 has one of the lowest M PID values (6%) in its family, and therefore this virus has one of the hardest outer shells, which makes it resistant to antimicrobial enzymes in body fluid. While this is likely responsible for its contagiousness, the risks of creating an attenuated virus with a more disordered M are discussed.