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Rotavirus Species B Encodes a Functional Fusion-Associated Small Transmembrane Protein.
Diller JR, Parrington HM, Patton JT, Ogden KM
(2019) J Virol 93:
MeSH Terms: Amino Acid Sequence, Animals, Cell Line, Cytopathogenic Effect, Viral, Giant Cells, Host-Pathogen Interactions, Humans, Membrane Proteins, Protein Binding, Protein Interaction Domains and Motifs, Rotavirus, Rotavirus Infections, Viral Nonstructural Proteins, Viral Proteins
Show Abstract · Added March 3, 2020
Rotavirus is an important cause of diarrheal disease in young mammals. Rotavirus species A (RVA) causes most human rotavirus diarrheal disease and primarily affects infants and young children. Rotavirus species B (RVB) has been associated with sporadic outbreaks of human adult diarrheal disease. RVA and RVB are predicted to encode mostly homologous proteins but differ significantly in the proteins encoded by the NSP1 gene. In the case of RVB, the NSP1 gene encodes two putative protein products of unknown function, NSP1-1 and NSP1-2. We demonstrate that human RVB NSP1-1 mediates syncytium formation in cultured human cells. Based on sequence alignment, NSP1-1 proteins from species B, G, and I contain features consistent with fusion-associated small transmembrane (FAST) proteins, which have previously been identified in other genera of the family. Like some other FAST proteins, RVB NSP1-1 is predicted to have an N-terminal myristoyl modification. Addition of an N-terminal FLAG peptide disrupts NSP1-1-mediated fusion. NSP1-1 from a human RVB mediates fusion of human cells but not hamster cells and, thus, may serve as a species tropism determinant. NSP1-1 also can enhance RVA replication in human cells, both in single-cycle infection studies and during a multicycle time course in the presence of fetal bovine serum, which inhibits rotavirus spread. These findings suggest potential yet untested roles for NSP1-1 in RVB species tropism, immune evasion, and pathogenesis. While species A rotavirus is commonly associated with diarrheal disease in young children, species B rotavirus has caused sporadic outbreaks of adult diarrheal disease. A major genetic difference between species A and B rotaviruses is the NSP1 gene, which encodes two proteins for species B rotavirus. We demonstrate that the smaller of these proteins, NSP1-1, can mediate fusion of cultured human cells. Comparison with viral proteins of similar function provides insight into NSP1-1 domain organization and fusion mechanism. These comparisons suggest that there is a fatty acid modification at the amino terminus of the protein, and our results show that an intact amino terminus is required for NSP1-1-mediated fusion. NSP1-1 from a human virus mediates fusion of human cells, but not hamster cells, and enhances species A rotavirus replication in culture. These findings suggest potential, but currently untested, roles for NSP1-1 in RVB host species tropism, immune evasion, and pathogenesis.
Copyright © 2019 American Society for Microbiology.
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14 MeSH Terms
The STAT5b Linker Domain Mediates the Selectivity of Catechol Bisphosphates for STAT5b over STAT5a.
Gräb J, Berg A, Blechschmidt L, Klüver B, Rubner S, Fu DY, Meiler J, Gräber M, Berg T
(2019) ACS Chem Biol 14: 796-805
MeSH Terms: Binding Sites, Catechols, Humans, Protein Binding, Protein Interaction Domains and Motifs, STAT5 Transcription Factor, Tumor Suppressor Proteins, src Homology Domains
Show Abstract · Added March 21, 2020
STAT family proteins are important mediators of cell signaling and represent therapeutic targets for the treatment of human diseases. Most STAT inhibitors target the protein-protein interaction domain, the SH2 domain, but specificity for a single STAT protein is often limited. Recently, we developed catechol bisphosphates as the first inhibitors of STAT5b demonstrated to exhibit a high degree of selectivity over the close homologue STAT5a. Here, we show that the amino acid in position 566 of the linker domain, not the SH2 domain, is the main determinant of specificity. Arg566 in wild-type STAT5b favors tight binding of catechol bisphosphates, while Trp566 in wild-type STAT5a does not. Amino acid 566 also determines the affinity for a tyrosine-phosphorylated peptide derived from the EPO receptor for STAT5a and STAT5b, demonstrating the functional relevance of the STAT5 linker domain for the adjacent SH2 domain. These results provide the first demonstration that a residue in the linker domain can determine the affinity of nonpeptidic small-molecule inhibitors for the SH2 domain of STAT proteins. We propose targeting the interface between the SH2 domain and linker domain as a novel design approach for the development of potent and selective STAT inhibitors. In addition, our data suggest that the linker domain could contribute to the enigmatically divergent biological functions of the two STAT5 proteins.
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Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor-binding head domains.
Turner HL, Pallesen J, Lang S, Bangaru S, Urata S, Li S, Cottrell CA, Bowman CA, Crowe JE, Wilson IA, Ward AB
(2019) PLoS Biol 17: e3000139
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Neutralizing, Antibody Specificity, Baculoviridae, Binding Sites, Cloning, Molecular, Cryoelectron Microscopy, Gene Expression, Hemagglutinin Glycoproteins, Influenza Virus, Hydrogen Bonding, Immunoglobulin Fab Fragments, Influenza A virus, Molecular Docking Simulation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Recombinant Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Sf9 Cells, Spodoptera
Show Abstract · Added March 31, 2019
Seasonal influenza virus infections can cause significant morbidity and mortality, but the threat from the emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy (cryoEM) to decipher the mechanism of action of a potent HA head-directed monoclonal antibody (mAb) bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, prefusion conformation that typifies all HA structures to date. Instead, the antibody binds between HA head protomers to an epitope that must be partly or transiently exposed in the prefusion conformation. The "breathing" of the HA protomers is implied by the exposure of this epitope, which is consistent with metastability of class I fusion proteins. This structure likely therefore represents an early structural intermediate in the viral fusion process. Understanding the extent of transient exposure of conserved neutralizing epitopes also may lead to new opportunities to combat influenza that have not been appreciated previously.
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The Structure of the Bifunctional Everninomicin Biosynthetic Enzyme EvdMO1 Suggests Independent Activity of the Fused Methyltransferase-Oxidase Domains.
Starbird CA, Perry NA, Chen Q, Berndt S, Yamakawa I, Loukachevitch LV, Limbrick EM, Bachmann BO, Iverson TM, McCulloch KM
(2018) Biochemistry 57: 6827-6837
MeSH Terms: Amino Acid Sequence, Aminoglycosides, Bacterial Proteins, Biosynthetic Pathways, Catalytic Domain, Conserved Sequence, Crystallography, X-Ray, Gene Fusion, Genes, Bacterial, Methyltransferases, Micromonospora, Models, Molecular, Oxygenases, Protein Interaction Domains and Motifs, Sequence Homology, Amino Acid
Show Abstract · Added April 1, 2019
Members of the orthosomycin family of natural products are decorated polysaccharides with potent antibiotic activity and complex biosynthetic pathways. The defining feature of the orthosomycins is an orthoester linkage between carbohydrate moieties that is necessary for antibiotic activity and is likely formed by a family of conserved oxygenases. Everninomicins are octasaccharide orthosomycins produced by Micromonospora carbonacea that have two orthoester linkages and a methylenedioxy bridge, three features whose formation logically requires oxidative chemistry. Correspondingly, the evd gene cluster encoding everninomicin D encodes two monofunctional nonheme iron, α-ketoglutarate-dependent oxygenases and one bifunctional enzyme with an N-terminal methyltransferase domain and a C-terminal oxygenase domain. To investigate whether the activities of these domains are linked in the bifunctional enzyme EvdMO1, we determined the structure of the N-terminal methyltransferase domain to 1.1 Å and that of the full-length protein to 3.35 Å resolution. Both domains of EvdMO1 adopt the canonical folds of their respective superfamilies and are connected by a short linker. Each domain's active site is oriented such that it faces away from the other domain, and there is no evidence of a channel connecting the two. Our results support EvdMO1 working as a bifunctional enzyme with independent catalytic activities.
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Movement of the RecG Motor Domain upon DNA Binding Is Required for Efficient Fork Reversal.
Warren GM, Stein RA, Mchaourab HS, Eichman BF
(2018) Int J Mol Sci 19:
MeSH Terms: DNA, DNA Helicases, DNA Replication, DNA-Binding Proteins, Models, Molecular, Molecular Conformation, Mutation, Nucleic Acid Conformation, Protein Binding, Protein Interaction Domains and Motifs, Structure-Activity Relationship
Show Abstract · Added August 26, 2019
RecG catalyzes reversal of stalled replication forks in response to replication stress in bacteria. The protein contains a fork recognition ("wedge") domain that binds branched DNA and a superfamily II (SF2) ATPase motor that drives translocation on double-stranded (ds)DNA. The mechanism by which the wedge and motor domains collaborate to catalyze fork reversal in RecG and analogous eukaryotic fork remodelers is unknown. Here, we used electron paramagnetic resonance (EPR) spectroscopy to probe conformational changes between the wedge and ATPase domains in response to fork DNA binding by RecG. Upon binding DNA, the ATPase-C lobe moves away from both the wedge and ATPase-N domains. This conformational change is consistent with a model of RecG fully engaged with a DNA fork substrate constructed from a crystal structure of RecG bound to a DNA junction together with recent cryo-electron microscopy (EM) structures of chromatin remodelers in complex with dsDNA. We show by mutational analysis that a conserved loop within the translocation in RecG (TRG) motif that was unstructured in the RecG crystal structure is essential for fork reversal and DNA-dependent conformational changes. Together, this work helps provide a more coherent model of fork binding and remodeling by RecG and related eukaryotic enzymes.
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Integrated Structural Biology for α-Helical Membrane Protein Structure Determination.
Xia Y, Fischer AW, Teixeira P, Weiner B, Meiler J
(2018) Structure 26: 657-666.e2
MeSH Terms: Algorithms, Binding Sites, Electron Spin Resonance Spectroscopy, Humans, Membrane Proteins, Microscopy, Electron, Models, Molecular, Monte Carlo Method, Nuclear Magnetic Resonance, Biomolecular, Protein Binding, Protein Conformation, alpha-Helical, Protein Folding, Protein Interaction Domains and Motifs, Rhodopsin, Thermodynamics
Show Abstract · Added March 17, 2018
While great progress has been made, only 10% of the nearly 1,000 integral, α-helical, multi-span membrane protein families are represented by at least one experimentally determined structure in the PDB. Previously, we developed the algorithm BCL::MP-Fold, which samples the large conformational space of membrane proteins de novo by assembling predicted secondary structure elements guided by knowledge-based potentials. Here, we present a case study of rhodopsin fold determination by integrating sparse and/or low-resolution restraints from multiple experimental techniques including electron microscopy, electron paramagnetic resonance spectroscopy, and nuclear magnetic resonance spectroscopy. Simultaneous incorporation of orthogonal experimental restraints not only significantly improved the sampling accuracy but also allowed identification of the correct fold, which is demonstrated by a protein size-normalized transmembrane root-mean-square deviation as low as 1.2 Å. The protocol developed in this case study can be used for the determination of unknown membrane protein folds when limited experimental restraints are available.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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Mechanisms of receptor tyrosine kinase activation in cancer.
Du Z, Lovly CM
(2018) Mol Cancer 17: 58
MeSH Terms: Animals, Cell Transformation, Neoplastic, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Ligands, Molecular Targeted Therapy, Mutation, Neoplasms, Phosphorylation, Protein Binding, Protein Interaction Domains and Motifs, Protein Kinase Inhibitors, Protein Multimerization, Receptor Protein-Tyrosine Kinases, Signal Transduction
Show Abstract · Added September 10, 2020
Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR, HER2/ErbB2, and MET, amongst many others. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation. In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms whereby RTKs can be aberrantly activated in human cancers. Understanding of these mechanisms has important implications for selection of anti-cancer therapies.
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The C-terminal region of A-kinase anchor protein 350 (AKAP350A) enables formation of microtubule-nucleation centers and interacts with pericentriolar proteins.
Kolobova E, Roland JT, Lapierre LA, Williams JA, Mason TA, Goldenring JR
(2017) J Biol Chem 292: 20394-20409
MeSH Terms: A Kinase Anchor Proteins, Biomarkers, Cell Cycle Proteins, Cell Line, Centrosome, Cytoskeletal Proteins, Humans, Imaging, Three-Dimensional, Intracellular Signaling Peptides and Proteins, Luminescent Proteins, Microscopy, Electron, Transmission, Microtubule-Associated Proteins, Microtubule-Organizing Center, Models, Molecular, Nerve Tissue Proteins, Peptide Fragments, Phosphoproteins, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Protein Multimerization, Proteomics, RNA Interference, Recombinant Fusion Proteins, Recombinant Proteins, Two-Hybrid System Techniques
Show Abstract · Added April 3, 2018
Microtubules in animal cells assemble (nucleate) from both the centrosome and the cis-Golgi cisternae. A-kinase anchor protein 350 kDa (AKAP350A, also called AKAP450/CG-NAP/AKAP9) is a large scaffolding protein located at both the centrosome and Golgi apparatus. Previous findings have suggested that AKAP350 is important for microtubule dynamics at both locations, but how this scaffolding protein assembles microtubule nucleation machinery is unclear. Here, we found that overexpression of the C-terminal third of AKAP350A, enhanced GFP-AKAP350A(2691-3907), induces the formation of multiple microtubule-nucleation centers (MTNCs). Nevertheless, these induced MTNCs lacked "true" centriole proteins, such as Cep135. Mapping analysis with AKAP350A truncations demonstrated that AKAP350A contains discrete regions responsible for promoting or inhibiting the formation of multiple MTNCs. Moreover, GFP-AKAP350A(2691-3907) recruited several pericentriolar proteins to MTNCs, including γ-tubulin, pericentrin, Cep68, Cep170, and Cdk5RAP2. Proteomic analysis indicated that Cdk5RAP2 and Cep170 both interact with the microtubule nucleation-promoting region of AKAP350A, whereas Cep68 interacts with the distal C-terminal AKAP350A region. Yeast two-hybrid assays established a direct interaction of Cep170 with AKAP350A. Super-resolution and deconvolution microscopy analyses were performed to define the association of AKAP350A with centrosomes, and these studies disclosed that AKAP350A spans the bridge between centrioles, co-localizing with rootletin and Cep68 in the linker region. siRNA-mediated depletion of AKAP350A caused displacement of both Cep68 and Cep170 from the centrosome. These results suggest that AKAP350A acts as a scaffold for factors involved in microtubule nucleation at the centrosome and coordinates the assembly of protein complexes associating with the intercentriolar bridge.
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25 MeSH Terms
Dodecyl-β-melibioside Detergent Micelles as a Medium for Membrane Proteins.
Hutchison JM, Lu Z, Li GC, Travis B, Mittal R, Deatherage CL, Sanders CR
(2017) Biochemistry 56: 5481-5484
MeSH Terms: Amyloid beta-Protein Precursor, Detergents, Diacylglycerol Kinase, Disaccharides, Dynamic Light Scattering, Enzyme Stability, Escherichia coli Proteins, Glucosides, Glycolipids, Hot Temperature, Humans, Micelles, Myelin Proteins, Nuclear Magnetic Resonance, Biomolecular, Particle Size, Peptide Fragments, Protein Interaction Domains and Motifs, Protein Stability, Receptor, Notch1
Show Abstract · Added November 21, 2018
There remains a need for new non-ionic detergents that are suitable for use in biochemical and biophysical studies of membrane proteins. Here we explore the properties of n-dodecyl-β-melibioside (β-DDMB) micelles as a medium for membrane proteins. Melibiose is d-galactose-α(1→6)-d-glucose. Light scattering showed the β-DDMB micelle to be roughly 30 kDa smaller than micelles formed by the commonly used n-dodecyl-β-maltoside (β-DDM). β-DDMB stabilized diacylglycerol kinase (DAGK) against thermal inactivation. Moreover, activity assays conducted using aliquots of DAGK purified into β-DDMB yielded activities that were 40% higher than those of DAGK purified into β-DDM. β-DDMB yielded similar or better TROSY-HSQC NMR spectra for two single-pass membrane proteins and the tetraspan membrane protein peripheral myelin protein 22. β-DDMB appears be a useful addition to the toolbox of non-ionic detergents available for membrane protein research.
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Building collagen IV smart scaffolds on the outside of cells.
Brown KL, Cummings CF, Vanacore RM, Hudson BG
(2017) Protein Sci 26: 2151-2161
MeSH Terms: Amino Acid Motifs, Amino Acid Oxidoreductases, Animals, Antigens, Neoplasm, Basement Membrane, Collagen Type IV, Eukaryotic Cells, Extracellular Matrix, Gene Expression Regulation, Humans, Peroxidases, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Structure, Secondary, Protein Subunits, Receptors, Interleukin-1
Show Abstract · Added November 2, 2017
Collagen IV scaffolds assemble through an intricate pathway that begins intracellularly and is completed extracellularly. Multiple intracellular enzymes act in concert to assemble collagen IV protomers, the building blocks of collagen IV scaffolds. After being secreted from cells, protomers are activated to initiate oligomerization, forming insoluble networks that are structurally reinforced with covalent crosslinks. Within these networks, embedded binding sites along the length of the protomer lead to the "decoration" of collagen IV triple helix with numerous functional molecules. We refer to these networks as "smart" scaffolds, which as a component of the basement membrane enable the development and function of multicellular tissues in all animal phyla. In this review, we present key molecular mechanisms that drive the assembly of collagen IV smart scaffolds.
© 2017 The Protein Society.
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16 MeSH Terms