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166 results on '"Veverka, Vaclav"'

1. Structural basis of MICAL autoinhibition

Author

Horvath, Matej, Schrofel, Adam, Kowalska, Karolina, Sabo, Jan, Vlasak, Jonas, Nourisanami, Farahdokht, Sobol, Margarita, Pinkas, Daniel, Knapp, Krystof, Koupilova, Nicola, Novacek, Jiri, Veverka, Vaclav, Lansky, Zdenek, and Rozbesky, Daniel

Published
2024
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4. Development and Characterization of a Chronic Hepatitis B Murine Model With a Mutation in the START Codon of an HBV Polymerase

Author

VANEKOVA, Lenka, POLIDAROVA, Marketa, CHARVAT, Vilem, VAVRINA, Zdenek, VEVERKA, Vaclav, BIRKUS, Gabriel, and BRAZDOVA, Andrea

Subjects
Physiology, Articles, General Medicine
Abstract

Chronic hepatitis B (CHB) is caused by the Hepatitis B virus (HBV) and affects millions of people worldwide. Developing an effective CHB therapy requires using in vivo screening methods, such as mouse models reflecting CHB based on hydrodynamic delivery of plasmid vectors containing a replication-competent HBV genome. However, long-term expression of HBV proteins is accompanied by production of progeny virions, thereby requiring a Biosafety Level (BSL) 3 animal facility. In the present study, we introduced a point mutation in the START codon of the HBV polymerase to develop a mouse model reflecting chronic hepatitis B infection without formation of viral progeny. We induced the mouse model by hydrodynamic injection of adeno-associated virus plasmid vector (pAAV) and minicircle plasmid (pMC) constructs into C57Bl/6 and C3H/HeN mouse strains, monitoring HBV antigens and antibodies in blood by enzyme-linked immunosorbent assay and analyzing liver expression of HBV core antigen by immunohistology. Persisting expression of viral antigens over 140 days (study endpoint) was observed only in the C3H/HeN mouse strain when using pAAV/1.2HBV-A and pMC/1.0HBV-D with pre-C and pre-S recombination sites. In addition, pAAV/1.2HBV-A in C3H/HeN sustained HBV core antigen positivity up to the study endpoint in C3H/HeN mice. Moreover, introducing the point mutation in the START codon of polymerase effectively prevented the formation of viral progeny. Our study establishes an accessible and affordable experimental paradigm for developing a robust mouse model reflecting CHB suitable for preclinical testing of anti-HBV therapeutics in a BSL2 animal facility.

Published
2023
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14. Characterization of the Interaction of Sclerostin with the Low Density Lipoprotein Receptor-related Protein (LRP) Family of Wnt Co-receptors

Author

Holdsworth, Gill, Slocombe, Patrick, Doyle, Carl, Sweeney, Bernadette, Veverka, Vaclav, Le Riche, Kelly, Franklin, Richard J., Compson, Joanne, Brookings, Daniel, Turner, James, Kennedy, Jeffery, Garlish, Rachael, Shi, Jiye, Newnham, Laura, McMillan, David, Muzylak, Mariusz, Carr, Mark D., Henry, Alistair J., Ceska, Thomas, and Robinson, Martyn K.

Published
2012
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19. A ubiquitous disordered protein interaction module orchestrates transcription elongation

Author

Cermakova, Katerina, primary, Demeulemeester, Jonas, additional, Lux, Vanda, additional, Nedomova, Monika, additional, Goldman, Seth R., additional, Smith, Eric A., additional, Srb, Pavel, additional, Hexnerova, Rozalie, additional, Fabry, Milan, additional, Madlikova, Marcela, additional, Horejsi, Magdalena, additional, De Rijck, Jan, additional, Debyser, Zeger, additional, Adelman, Karen, additional, Hodges, H. Courtney, additional, and Veverka, Vaclav, additional

Published
2021
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23. Dominant-negative SMARCA4 missense mutations alter the accessibility landscape of tissue-unrestricted enhancers

Author

Hodges, H. Courtney, Stanton, Benjamin Z., Cermakova, Katerina, Chang, Chiung-Ying, Miller, Erik L., Kirkland, Jacob G., Ku, Wai Lim, Veverka, Vaclav, Zhao, Keji, and Crabtree, Gerald R.

Subjects
Epigenomics, Heterozygote, Genotype, Mutation, Missense, Polycomb-Group Proteins, Mice, Transgenic, Article, chromatin remodeling, Mice, Neoplasms, Animals, Humans, Cancer, Genes, Dominant, Adenosine Triphosphatases, Sequence Analysis, RNA, DNA Helicases, Nuclear Proteins, Mouse Embryonic Stem Cells, Chromatin Assembly and Disassembly, Chromatin, Culture Media, Enhancer Elements, Genetic, Multivariate Analysis, Mutation, enhancers, Transcription Factors
Abstract

Mutation of SMARCA4 (BRG1), the ATPase of BAF (mSWI/SNF) and PBAF complexes, contributes to a range of malignancies and neurologic disorders. Unfortunately, the effects of SMARCA4 missense mutations have remained uncertain. Here we show that SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of remodeling. We find that heterozygous expression of mutants alters the open chromatin landscape at thousands of sites across the genome. Loss of DNA accessibility does not directly overlap with Polycomb accumulation, but is enriched in 'A compartments' at active enhancers, which lose H3K27ac but not H3K4me1. Affected positions include hundreds of sites identified as superenhancers in many tissues. Dominant-negative mutation induces pro-oncogenic expression changes, including increased expression of Myc and its target genes. Together, our data suggest that disruption of enhancer accessibility represents a key source of altered function in disorders with SMARCA4 mutations in a wide variety of tissues.

Published
2017

27. Structural characterization of CAS SH3 domain selectivity and regulation reveals new CAS interaction partners

Author

Gemperle, Jakub, Hexnerova, Rozlie, Lepsik, Martin, Tesina, Petr, Dibus, Michal, Novotny, Marian, Brabek, Jan, Veverka, Vaclav, and Rosel, Daniel

Subjects
p130Cas, Binding Sites, Science, macromolecular substances, Ligands, Proto-Oncogene Mas, environment and public health, Article, eye diseases, src Homology Domains, SH3, Crk-Associated Substrate Protein, embryonic structures, Humans, Medicine, BCAR1, Amino Acid Sequence, Amino Acids, Phosphorylation, human activities, Src, Protein Binding, Signal Transduction
Abstract

CAS is a docking protein downstream of the proto-oncogene Src with a role in invasion and metastasis of cancer cells. The CAS SH3 domain is indispensable for CAS-mediated signaling, but structural aspects of CAS SH3 ligand binding and regulation are not well understood. Here, we identified the consensus CAS SH3 binding motif and structurally characterized the CAS SH3 domain in complex with ligand. We revealed the requirement for an uncommon centrally localized lysine residue at position +2 of CAS SH3 ligands and two rather dissimilar optional anchoring residues, leucine and arginine, at position +5. We further expanded the knowledge of CAS SH3 ligand binding regulation by manipulating tyrosine 12 phosphorylation and confirmed the negative role of this phosphorylation on CAS SH3 ligand binding. Finally, by exploiting the newly identified binding requirements of the CAS SH3 domain, we predicted and experimentally verified two novel CAS SH3 binding partners, DOK7 and GLIS2.

Published
2017
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35. The redox‐active site of thioredoxin is directly involved in apoptosis signal‐regulating kinase 1 binding that is modulated by oxidative stress.

Author

Psenakova, Katarina, Hexnerova, Rozalie, Srb, Pavel, Obsilova, Veronika, Veverka, Vaclav, and Obsil, Tomas

Subjects
THIOREDOXIN, OXIDATIVE stress, NUCLEAR magnetic resonance spectroscopy, MOLECULAR switches, DRUG design
Abstract

Apoptosis signal‐regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen‐activated protein kinase kinase kinase 5, which mediates various stress signals including oxidative stress. The catalytic activity of ASK1 is tightly controlled by oligomerization and binding of several cofactors. Among these cofactors, thioredoxin stands out as the most important ASK1 inhibitor, but only the reduced form of thioredoxin inhibits ASK1 by direct binding to its N‐terminal domain. In addition, oxidation‐driven thioredoxin dissociation is the key event in oxidative stress‐mediated ASK1 activation. However, the structural mechanism of ASK1 regulation by thioredoxin remains unknown. Here, we report the characterization of the ASK1 domain responsible for thioredoxin binding and its complex using NMR spectroscopy and chemical cross‐linking, thus providing the molecular basis for ASK1: thioredoxin complex dissociation under oxidative stress conditions. Our data reveal that the N‐terminal domain of ASK1 adopts a fold resembling the thioredoxin structure while retaining substantial conformational plasticity at the thioredoxin‐binding interface. Although oxidative stress induces relatively moderate structural changes in thioredoxin, the formation of intramolecular disulfide bridges leads to a considerable conformational rearrangement of the thioredoxin‐binding interface on ASK1. Moreover, the cysteine residue at position 250 of ASK1 is the key element of this molecular switch. Finally, our results show that the redox‐active site of thioredoxin is directly involved in ASK1 binding that is modulated by oxidative stress, thereby identifying a key target for the structure‐based drug design. [ABSTRACT FROM AUTHOR]

Published
2020
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36. PI(4,5)P2 controls plasma membrane PI4P and PS levels via ORP5/8 recruitment to ER–PM contact sites

Author

Sohn, Mira, primary, Korzeniowski, Marek, additional, Zewe, James P., additional, Wills, Rachel C., additional, Hammond, Gerald R.V., additional, Humpolickova, Jana, additional, Vrzal, Lukas, additional, Chalupska, Dominika, additional, Veverka, Vaclav, additional, Fairn, Gregory D., additional, Boura, Evzen, additional, and Balla, Tamas, additional

Published
2018
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39. Human DNA-Damage-Inducible 2 Protein Is Structurally and Functionally Distinct from Its Yeast Ortholog

Author

Siva, Monika, Svoboda, Michal, Veverka, Vaclav, Trempe, Jean-Francois, Hofmann, Kay, Kozisek, Milan, Hexnerova, Rozalie, Sedlak, Frantisek, Belza, Jan, Brynda, Jiri, Sacha, Pavel, Hubalek, Martin, Starkova, Jana, Flaisigova, Iva, Konvalinka, Jan, Saskova, Klara Grantz, Siva, Monika, Svoboda, Michal, Veverka, Vaclav, Trempe, Jean-Francois, Hofmann, Kay, Kozisek, Milan, Hexnerova, Rozalie, Sedlak, Frantisek, Belza, Jan, Brynda, Jiri, Sacha, Pavel, Hubalek, Martin, Starkova, Jana, Flaisigova, Iva, Konvalinka, Jan, and Saskova, Klara Grantz

Abstract

Although Ddi1-like proteins are conserved among eukaryotes, their biological functions remain poorly characterized. Yeast Ddi1 has been implicated in cell cycle regulation, DNA-damage response, and exocytosis. By virtue of its ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains, it has been proposed to serve as a proteasomal shuttle factor. All Ddi1-like family members also contain a highly conserved retroviral protease-like (RVP) domain with unknown substrate specificity. While the structure and biological function of yeast Ddi1 have been investigated, no such analysis is available for the human homologs. To address this, we solved the 3D structures of the human Ddi2 UBL and RVP domains and identified a new helical domain that extends on either side of the RVP dimer. While Ddi1-like proteins from all vertebrates lack a UBA domain, we identify a novel ubiquitin-interacting motif (UIM) located at the C-terminus of the protein. The UIM showed a weak yet specific affinity towards ubiquitin, as did the Ddi2 UBL domain. However, the full-length Ddi2 protein is unable to bind to di-ubiquitin chains. While proteomic analysis revealed no activity, implying that the protease requires other factors for activation, our structural characterization of all domains of human Ddi2 sets the stage for further characterization.

Published
2016

40. Conformational Heterogeneity in Antibody-Protein Antigen Recognition: IMPLICATIONS FOR HIGH AFFINITY PROTEIN COMPLEX FORMATION

Author

Addis, Philip W., Hall, Catherine J., Bruton, Shaun, Veverka, Vaclav, Wilkinson, Ian C., Muskett, Frederick W., Renshaw, Philip S., Prosser, Christine E., Carrington, Bruce, Lawson, Alastair D. G., Griffin, Robert, Taylor, Richard J., Waters, Lorna C., Henry, Alistair J., and Carr, Mark D.

Subjects
Interleukin-6, animal diseases, Interleukin-1beta, Molecular Sequence Data, Antibody Affinity, chemical and pharmacologic phenomena, Antigen-Antibody Complex, biochemical phenomena, metabolism, and nutrition, Antibodies, Monoclonal, Humanized, Protein Structure, Secondary, Immunoglobulin Fab Fragments, Protein Structure and Folding, bacteria, Humans, Amino Acid Sequence, Antigens, Nuclear Magnetic Resonance, Biomolecular
Abstract

Specific, high affinity protein-protein interactions lie at the heart of many essential biological processes, including the recognition of an apparently limitless range of foreign proteins by natural antibodies, which has been exploited to develop therapeutic antibodies. To mediate biological processes, high affinity protein complexes need to form on appropriate, relatively rapid timescales, which presents a challenge for the productive engagement of complexes with large and complex contact surfaces (∼600-1800 Å(2)). We have obtained comprehensive backbone NMR assignments for two distinct, high affinity antibody fragments (single chain variable and antigen-binding (Fab) fragments), which recognize the structurally diverse cytokines interleukin-1β (IL-1β, β-sheet) and interleukin-6 (IL-6, α-helical). NMR studies have revealed that the hearts of the antigen binding sites in both free anti-IL-1β Fab and anti-IL-6 single chain variable exist in multiple conformations, which interconvert on a timescale comparable with the rates of antibody-antigen complex formation. In addition, we have identified a conserved antigen binding-induced change in the orientation of the two variable domains. The observed conformational heterogeneity and slow dynamics at protein antigen binding sites appears to be a conserved feature of many high affinity protein-protein interfaces structurally characterized by NMR, suggesting an essential role in protein complex formation. We propose that this behavior may reflect a soft capture, protein-protein docking mechanism, facilitating formation of high affinity protein complexes on a timescale consistent with biological processes.

Published
2014

41. Calcium-Driven Folding of RTX Domain β-Rolls Ratchets Translocation of RTX Proteins through Type I Secretion Ducts

Author

Bumba, Ladislav, primary, Masin, Jiri, additional, Macek, Pavel, additional, Wald, Tomas, additional, Motlova, Lucia, additional, Bibova, Ilona, additional, Klimova, Nela, additional, Bednarova, Lucie, additional, Veverka, Vaclav, additional, Kachala, Michael, additional, Svergun, Dmitri I., additional, Barinka, Cyril, additional, and Sebo, Peter, additional

Published
2016
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42. Structural insights and in vitro reconstitution of membrane targeting and activation of human PI4KB by the ACBD3 protein

Author

Klima, Martin, primary, Tóth, Dániel J., additional, Hexnerova, Rozalie, additional, Baumlova, Adriana, additional, Chalupska, Dominika, additional, Tykvart, Jan, additional, Rezabkova, Lenka, additional, Sengupta, Nivedita, additional, Man, Petr, additional, Dubankova, Anna, additional, Humpolickova, Jana, additional, Nencka, Radim, additional, Veverka, Vaclav, additional, Balla, Tamas, additional, and Boura, Evzen, additional

Published
2016
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45. Conformational Heterogeneity in Antibody-Protein Antigen Recognition

Author

Addis, Philip W., primary, Hall, Catherine J., additional, Bruton, Shaun, additional, Veverka, Vaclav, additional, Wilkinson, Ian C., additional, Muskett, Frederick W., additional, Renshaw, Philip S., additional, Prosser, Christine E., additional, Carrington, Bruce, additional, Lawson, Alastair D.G., additional, Griffin, Robert, additional, Taylor, Richard J., additional, Waters, Lorna C., additional, Henry, Alistair J., additional, and Carr, Mark D., additional

Published
2014
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46. Structure and Interactions of the Human Programmed Cell Death 1 Receptor

Author

Cheng, Xiaoxiao, Veverka, Vaclav, Radhakrishnan, Anand, Waters, Lorna C., Muskett, Frederick W., Morgan, Sara H., Huo, Jiandong, Yu, Chao, Evans, Edward J., Leslie, Alasdair J., Griffiths, Meryn, Stubberfield, Colin, Griffin, Robert, Henry, Alistair J., Jansson, Andreas, Ladbury, John E., Ikemizu, Shinji, Carr, Mark D., Davis, Simon J., Cheng, Xiaoxiao, Veverka, Vaclav, Radhakrishnan, Anand, Waters, Lorna C., Muskett, Frederick W., Morgan, Sara H., Huo, Jiandong, Yu, Chao, Evans, Edward J., Leslie, Alasdair J., Griffiths, Meryn, Stubberfield, Colin, Griffin, Robert, Henry, Alistair J., Jansson, Andreas, Ladbury, John E., Ikemizu, Shinji, Carr, Mark D., and Davis, Simon J.

Abstract

PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC' sheet, which is flexible and completely lacks a C '' strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC' sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1.ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3-4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.

Published
2013
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47. Intrinsically Disordered Enamel Matrix Protein Ameloblastin Forms Ribbon-like Supramolecular Structures via an N-terminal Segment Encoded by Exon 5

Author

Wald, Tomas, primary, Osickova, Adriana, additional, Sulc, Miroslav, additional, Benada, Oldrich, additional, Semeradtova, Alena, additional, Rezabkova, Lenka, additional, Veverka, Vaclav, additional, Bednarova, Lucie, additional, Maly, Jan, additional, Macek, Pavel, additional, Sebo, Peter, additional, Slaby, Ivan, additional, Vondrasek, Jiri, additional, and Osicka, Radim, additional

Published
2013
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48. Corrigendum to “The Discovery, Engineering and Characterisation of a Highly Potent Anti-Human IL-13 Fab Fragment Designed for Administration by Inhalation” [J. Mol. Biol. 425 (2013), 577–593]

Author

Lightwood, Daniel, primary, O'Dowd, Victoria, additional, Carrington, Bruce, additional, Veverka, Vaclav, additional, Carr, Mark D., additional, Tservistas, Markus, additional, Henry, Alistair J., additional, Smith, Bryan, additional, Tyson, Kerry, additional, Lamour, Sabrina, additional, Bracher, Marguerite, additional, Sarkar, Kaushik, additional, Turner, Alison, additional, Lawson, Alastair D., additional, Bourne, Tim, additional, Gozzard, Neil, additional, and Palframan, Roger, additional

Published
2013
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49. Structure and Interactions of the Human Programmed Cell Death 1 Receptor

Author

Cheng, Xiaoxiao, primary, Veverka, Vaclav, additional, Radhakrishnan, Anand, additional, Waters, Lorna C., additional, Muskett, Frederick W., additional, Morgan, Sara H., additional, Huo, Jiandong, additional, Yu, Chao, additional, Evans, Edward J., additional, Leslie, Alasdair J., additional, Griffiths, Meryn, additional, Stubberfield, Colin, additional, Griffin, Robert, additional, Henry, Alistair J., additional, Jansson, Andreas, additional, Ladbury, John E., additional, Ikemizu, Shinji, additional, Carr, Mark D., additional, and Davis, Simon J., additional

Published
2013
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50. The Discovery, Engineering and Characterisation of a Highly Potent Anti-Human IL-13 Fab Fragment Designed for Administration by Inhalation

Author

Lightwood, Daniel, primary, O'Dowd, Victoria, additional, Carrington, Bruce, additional, Veverka, Vaclav, additional, Carr, Mark D., additional, Tservistas, Markus, additional, Henry, Alistair J., additional, Smith, Bryan, additional, Tyson, Kerry, additional, Lamour, Sabrina, additional, Sarkar, Kaushik, additional, Turner, Alison, additional, Lawson, Alastair D., additional, Bourne, Tim, additional, Gozzard, Neil, additional, and Palframan, Roger, additional

Published
2013
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