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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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15 MeSH Terms
Gene Regulatory Enhancers with Evolutionarily Conserved Activity Are More Pleiotropic than Those with Species-Specific Activity.
Fish A, Chen L, Capra JA
(2017) Genome Biol Evol 9: 2615-2625
MeSH Terms: Animals, Callithrix, Cats, Cattle, Conserved Sequence, Databases, Genetic, Dogs, Enhancer Elements, Genetic, Evolution, Molecular, Genetic Pleiotropy, Histones, Humans, Macaca mulatta, Mice, Rabbits, Rats, Swine
Show Abstract · Added March 14, 2018
Studies of regulatory activity and gene expression have revealed an intriguing dichotomy: There is substantial turnover in the regulatory activity of orthologous sequences between species; however, the expression level of orthologous genes is largely conserved. Understanding how distal regulatory elements, for example, enhancers, evolve and function is critical, as alterations in gene expression levels can drive the development of both complex disease and functional divergence between species. In this study, we investigated determinants of the conservation of regulatory enhancer activity for orthologous sequences across mammalian evolution. Using liver enhancers identified from genome-wide histone modification profiles in ten diverse mammalian species, we compared orthologous sequences that exhibited regulatory activity in all species (conserved-activity enhancers) to shared sequences active only in a single species (species-specific-activity enhancers). Conserved-activity enhancers have greater regulatory potential than species-specific-activity enhancers, as quantified by both the density and diversity of transcription factor binding motifs. Consistent with their greater regulatory potential, conserved-activity enhancers have greater regulatory activity in humans than species-specific-activity enhancers: They are active across more cellular contexts, and they regulate more genes than species-specific-activity enhancers. Furthermore, the genes regulated by conserved-activity enhancers are expressed in more tissues and are less tolerant of loss-of-function mutations than those targeted by species-specific-activity enhancers. These consistent results across various stages of gene regulation demonstrate that conserved-activity enhancers are more pleiotropic than their species-specific-activity counterparts. This suggests that pleiotropy is associated with the conservation of regulatory across mammalian evolution.
© The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
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17 MeSH Terms
Use of a neutralizing antibody helps identify structural features critical for binding of toxin TcdA to the host cell surface.
Kroh HK, Chandrasekaran R, Rosenthal K, Woods R, Jin X, Ohi MD, Nyborg AC, Rainey GJ, Warrener P, Spiller BW, Lacy DB
(2017) J Biol Chem 292: 14401-14412
MeSH Terms: Amino Acid Sequence, Anti-Bacterial Agents, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Bacterial Proteins, Bacterial Toxins, Binding Sites, Antibody, Caco-2 Cells, Clostridium difficile, Conserved Sequence, Crystallography, X-Ray, Enterocytes, Enterotoxins, Epitope Mapping, Glucosyltransferases, Humans, Immunoglobulin Fab Fragments, Models, Molecular, Peptide Fragments, Protein Conformation, Protein Interaction Domains and Motifs, Recombinant Proteins, Repetitive Sequences, Amino Acid
Show Abstract · Added March 15, 2018
is a clinically significant pathogen that causes mild-to-severe (and often recurrent) colon infections. Disease symptoms stem from the activities of two large, multidomain toxins known as TcdA and TcdB. The toxins can bind, enter, and perturb host cell function through a multistep mechanism of receptor binding, endocytosis, pore formation, autoproteolysis, and glucosyltransferase-mediated modification of host substrates. Monoclonal antibodies that neutralize toxin activity provide a survival benefit in preclinical animal models and prevent recurrent infections in human clinical trials. However, the molecular mechanisms involved in these neutralizing activities are unclear. To this end, we performed structural studies on a neutralizing monoclonal antibody, PA50, a humanized mAb with both potent and broad-spectrum neutralizing activity, in complex with TcdA. Electron microscopy imaging and multiangle light-scattering analysis revealed that PA50 binds multiple sites on the TcdA C-terminal combined repetitive oligopeptides (CROPs) domain. A crystal structure of two PA50 Fabs bound to a segment of the TcdA CROPs helped define a conserved epitope that is distinct from previously identified carbohydrate-binding sites. Binding of TcdA to the host cell surface was directly blocked by either PA50 mAb or Fab and suggested that receptor blockade is the mechanism by which PA50 neutralizes TcdA. These findings highlight the importance of the CROPs C terminus in cell-surface binding and a role for neutralizing antibodies in defining structural features critical to a pathogen's mechanism of action. We conclude that PA50 protects host cells by blocking the binding of TcdA to cell surfaces.
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23 MeSH Terms
Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors.
Prokop S, Perry NA, Vishnivetskiy SA, Toth AD, Inoue A, Milligan G, Iverson TM, Hunyady L, Gurevich VV
(2017) Cell Signal 36: 98-107
MeSH Terms: Amino Acid Sequence, Animals, Arrestins, COS Cells, Cattle, Cercopithecus aethiops, Conserved Sequence, HEK293 Cells, Humans, Lysine, Mutant Proteins, Mutation, Protein Binding, Protein Structure, Secondary, Receptors, G-Protein-Coupled, Rhodopsin
Show Abstract · Added March 14, 2018
Non-visual arrestins interact with hundreds of different G protein-coupled receptors (GPCRs). Here we show that by introducing mutations into elements that directly bind receptors, the specificity of arrestin-3 can be altered. Several mutations in the two parts of the central "crest" of the arrestin molecule, middle-loop and C-loop, enhanced or reduced arrestin-3 interactions with several GPCRs in receptor subtype and functional state-specific manner. For example, the Lys139Ile substitution in the middle-loop dramatically enhanced the binding to inactive M muscarinic receptor, so that agonist activation of the M did not further increase arrestin-3 binding. Thus, the Lys139Ile mutation made arrestin-3 essentially an activation-independent binding partner of M, whereas its interactions with other receptors, including the β-adrenergic receptor and the D and D dopamine receptors, retained normal activation dependence. In contrast, the Ala248Val mutation enhanced agonist-induced arrestin-3 binding to the β-adrenergic and D dopamine receptors, while reducing its interaction with the D dopamine receptor. These mutations represent the first example of altering arrestin specificity via enhancement of the arrestin-receptor interactions rather than selective reduction of the binding to certain subtypes.
Copyright © 2017. Published by Elsevier Inc.
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16 MeSH Terms
Interaction of MYC with host cell factor-1 is mediated by the evolutionarily conserved Myc box IV motif.
Thomas LR, Foshage AM, Weissmiller AM, Popay TM, Grieb BC, Qualls SJ, Ng V, Carboneau B, Lorey S, Eischen CM, Tansey WP
(2016) Oncogene 35: 3613-8
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, Cell Transformation, Neoplastic, Conserved Sequence, Evolution, Molecular, HEK293 Cells, Host Cell Factor C1, Humans, Immunoprecipitation, Mice, Mutation, NIH 3T3 Cells, Protein Binding, Proto-Oncogene Proteins c-myc, Sequence Homology, Amino Acid
Show Abstract · Added March 26, 2019
The MYC family of oncogenes encodes a set of three related transcription factors that are overexpressed in many human tumors and contribute to the cancer-related deaths of more than 70,000 Americans every year. MYC proteins drive tumorigenesis by interacting with co-factors that enable them to regulate the expression of thousands of genes linked to cell growth, proliferation, metabolism and genome stability. One effective way to identify critical co-factors required for MYC function has been to focus on sequence motifs within MYC that are conserved throughout evolution, on the assumption that their conservation is driven by protein-protein interactions that are vital for MYC activity. In addition to their DNA-binding domains, MYC proteins carry five regions of high sequence conservation known as Myc boxes (Mb). To date, four of the Mb motifs (MbI, MbII, MbIIIa and MbIIIb) have had a molecular function assigned to them, but the precise role of the remaining Mb, MbIV, and the reason for its preservation in vertebrate Myc proteins, is unknown. Here, we show that MbIV is required for the association of MYC with the abundant transcriptional coregulator host cell factor-1 (HCF-1). We show that the invariant core of MbIV resembles the tetrapeptide HCF-binding motif (HBM) found in many HCF-interaction partners, and demonstrate that MYC interacts with HCF-1 in a manner indistinguishable from the prototypical HBM-containing protein VP16. Finally, we show that rationalized point mutations in MYC that disrupt interaction with HCF-1 attenuate the ability of MYC to drive tumorigenesis in mice. Together, these data expose a molecular function for MbIV and indicate that HCF-1 is an important co-factor for MYC.
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MeSH Terms
A Degenerate Cohort of Yeast Membrane Trafficking DUBs Mediates Cell Polarity and Survival.
Beckley JR, Chen JS, Yang Y, Peng J, Gould KL
(2015) Mol Cell Proteomics 14: 3132-41
MeSH Terms: Cell Membrane, Cell Polarity, Conserved Sequence, Endopeptidases, Humans, Protein Transport, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Substrate Specificity
Show Abstract · Added February 4, 2016
Deubiquitinating enzymes (DUBs), cysteine or metallo- proteases that cleave ubiquitin chains or protein conjugates, are present in nearly every cellular compartment, with overlapping protein domain structure, localization, and functions. We discovered a cohort of DUBs that are involved in membrane trafficking (ubp4, ubp5, ubp9, ubp15, and sst2) and found that loss of all five of these DUBs but not loss of any combination of four, significantly impacted cell viability in the fission yeast Schizosaccharomyces pombe (1). Here, we delineate the collective and individual functions and activities of these five conserved DUBs using comparative proteomics, biochemistry, and microscopy. We find these five DUBs are degenerate rather than redundant at the levels of cell morphology, substrate selectivity, ubiquitin chain specificity, and cell viability under stress. These studies reveal the complexity of interplay among these enzymes, providing a foundation for understanding DUB biology and providing another example of how cells utilize degeneracy to improve survival.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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9 MeSH Terms
Influence of Pathogenic Mutations on the Energetics of Translocon-Mediated Bilayer Integration of Transmembrane Helices.
Schlebach JP, Sanders CR
(2015) J Membr Biol 248: 371-81
MeSH Terms: Amino Acid Sequence, Animals, Cattle, Conserved Sequence, Cystic Fibrosis Transmembrane Conductance Regulator, Humans, KCNQ1 Potassium Channel, Lipid Bilayers, Mutation, Mutation, Missense, Myelin Proteins, Protein Structure, Secondary, Protein Transport, Receptors, Vasopressin, Rhodopsin, Thermodynamics
Show Abstract · Added November 21, 2018
Aberrant protein folding and assembly contribute to a number of diseases, and efforts to rationalize how pathogenic mutations cause this phenomenon represent an important imperative in biochemical research. However, for α-helical membrane proteins, this task is complicated by the fact that membrane proteins require intricate machinery to achieve structural and functional maturity under cellular conditions. In this work, we utilized the ΔG predictor algorithm ( www.dgpred.cbr.su.se ) to survey 470 known pathogenic mutations occurring in five misfolding-prone α-helical membrane proteins for their predicted effects on the translocon-mediated membrane integration of transmembrane helices, a critical step in biosynthesis and folding of nascent membrane proteins. The results suggest that about 10 % of these mutations are likely to have adverse effects on the topogenesis of nascent membrane proteins. These results suggest that the misfolding of a modest but nonetheless significant subset of pathogenic variants may begin at the translocon. Potential implications for therapeutic design and personalized medicine are discussed.
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DIPA-family coiled-coils bind conserved isoform-specific head domain of p120-catenin family: potential roles in hydrocephalus and heterotopia.
Markham NO, Doll CA, Dohn MR, Miller RK, Yu H, Coffey RJ, McCrea PD, Gamse JT, Reynolds AB
(2014) Mol Biol Cell 25: 2592-603
MeSH Terms: Adherens Junctions, Amino Acid Sequence, Animals, Cadherins, Catenins, Cell Line, Tumor, Conserved Sequence, Dogs, Gene Knockdown Techniques, HEK293 Cells, Humans, Hydrocephalus, Madin Darby Canine Kidney Cells, Molecular Sequence Data, Neural Tube Defects, Protein Isoforms, Protein Structure, Tertiary, Sequence Alignment, Zebrafish
Show Abstract · Added February 19, 2015
p120-catenin (p120) modulates adherens junction (AJ) dynamics by controlling the stability of classical cadherins. Among all p120 isoforms, p120-3A and p120-1A are the most prevalent. Both stabilize cadherins, but p120-3A is preferred in epithelia, whereas p120-1A takes precedence in neurons, fibroblasts, and macrophages. During epithelial-to-mesenchymal transition, E- to N-cadherin switching coincides with p120-3A to -1A alternative splicing. These isoforms differ by a 101-amino acid "head domain" comprising the p120-1A N-terminus. Although its exact role is unknown, the head domain likely mediates developmental and cancer-associated events linked to p120-1A expression (e.g., motility, invasion, metastasis). Here we identified delta-interacting protein A (DIPA) as the first head domain-specific binding partner and candidate mediator of isoform 1A activity. DIPA colocalizes with AJs in a p120-1A- but not 3A-dependent manner. Moreover, all DIPA family members (Ccdc85a, Ccdc85b/DIPA, and Ccdc85c) interact reciprocally with p120 family members (p120, δ-catenin, p0071, and ARVCF), suggesting significant functional overlap. During zebrafish neural tube development, both knockdown and overexpression of DIPA phenocopy N-cadherin mutations, an effect bearing functional ties to a reported mouse hydrocephalus phenotype associated with Ccdc85c. These studies identify a novel, highly conserved interaction between two protein families that may participate either individually or collectively in N-cadherin-mediated development.
© 2014 Markham et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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19 MeSH Terms
A common functional consequence of tumor-derived mutations within c-MYC.
Chakraborty AA, Scuoppo C, Dey S, Thomas LR, Lorey SL, Lowe SW, Tansey WP
(2015) Oncogene 34: 2406-9
MeSH Terms: Amino Acid Sequence, Animals, Cell Line, Tumor, Conserved Sequence, DNA, Humans, Lymphoma, Mice, Mutation, Missense, NIH 3T3 Cells, Proto-Oncogene Proteins c-myc
Show Abstract · Added February 12, 2015
The relevance of changes to the coding sequence of the c-MYC oncogene to malignancy is controversial. Overexpression of a pristine form of MYC is observed in many cancers and is sufficient to drive tumorigenesis in most contexts. Yet missense changes to MYC are found in ~50% of Burkitt's lymphomas, aggregate within an amino-terminal degron important for proteasomal destruction of MYC, and where examined profoundly enhance the tumorigenic properties of MYC in vitro and in vivo. Much of the controversy surrounding these mutants stems from the limited number of mutations that have been evaluated and their clustering within a single region of the MYC protein; the highly-conserved Myc box I (MbI) element. Here, by analysis of extant genomic data sets, we identify a previously unrecognized hotspot for tumor-associated MYC mutations, located in a conserved central portion of the protein. We show that, despite their distal location in MYC, mutations in this region precisely phenocopy those in MbI in terms of stability, in vitro transformation, growth-promoting properties, in vivo tumorigenesis and ability to escape p53-dependent tumor surveillance mechanisms. The striking parallels between the behavior of tumor-derived mutations in disparate regions of the MYC protein reveals that a common molecular process is disrupted by these mutations, implying an active role for these mutations in tumorigenesis and suggesting that different therapeutic strategies may be needed for treatment of lymphomas expressing wild type versus mutant forms of MYC protein.
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11 MeSH Terms
DNA methyltransferase 3a and mitogen-activated protein kinase signaling regulate the expression of fibroblast growth factor-inducible 14 (Fn14) during denervation-induced skeletal muscle atrophy.
Tajrishi MM, Shin J, Hetman M, Kumar A
(2014) J Biol Chem 289: 19985-99
MeSH Terms: Animals, Base Sequence, Conserved Sequence, CpG Islands, DNA, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Gene Expression, Gene Knockdown Techniques, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Models, Biological, Molecular Sequence Data, Muscle Denervation, Muscle, Skeletal, Muscular Atrophy, Promoter Regions, Genetic, RNA, Small Interfering, Receptors, Tumor Necrosis Factor, Sequence Homology, Nucleic Acid, Sp1 Transcription Factor, TWEAK Receptor, Transcription Factor AP-1
Show Abstract · Added October 30, 2014
The TWEAK-fibroblast growth factor-inducible 14 (Fn14) system is a critical regulator of denervation-induced skeletal muscle atrophy. Although the expression of Fn14 is a rate-limiting step in muscle atrophy on denervation, mechanisms regulating gene expression of Fn14 remain unknown. Methylation of CpG sites within promoter region is an important epigenetic mechanism for gene silencing. Our study demonstrates that Fn14 promoter contains a CpG island close to transcription start site. Fn14 promoter also contains multiple consensus DNA sequence for transcription factors activator protein 1 (AP1) and specificity protein 1 (SP1). Denervation diminishes overall genomic DNA methylation and causes hypomethylation at specific CpG sites in Fn14 promoter leading to the increased gene expression of Fn14 in skeletal muscle. Abundance of DNA methyltransferase 3a (Dnmt3a) and its interaction with Fn14 promoter are repressed in denervated skeletal muscle of mice. Overexpression of Dnmt3a inhibits the gene expression of Fn14 and attenuates skeletal muscle atrophy upon denervation. Denervation also causes the activation of ERK1/2, JNK1/2, and ERK5 MAPKs and AP1 and SP1, which stimulate the expression of Fn14 in skeletal muscle. Collectively, our study provides novel evidence that Dnmt3a and MAPK signaling regulate the levels of Fn14 in skeletal muscle on denervation.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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24 MeSH Terms