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Article ; Online: Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label treatment.

Hirt, Christian K / Booij, Tijmen H / Grob, Linda / Simmler, Patrik / Toussaint, Nora C / Keller, David / Taube, Doreen / Ludwig, Vanessa / Goryachkin, Alexander / Pauli, Chantal / Lenggenhager, Daniela / Stekhoven, Daniel J / Stirnimann, Christian U / Endhardt, Katharina / Ringnalda, Femke / Villiger, Lukas / Siebenhüner, Alexander / Karkampouna, Sofia / De Menna, Marta /

Beshay, Janette / Klett, Hagen / Kruithof-de Julio, Marianna / Schüler, Julia / Schwank, Gerald

Cell genomics

2022 Volume 2, Issue 2, Page(s) 100095

Abstract: Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor ... ...

Abstract	Pancreatic cancer (PDAC) is a highly aggressive malignancy for which the identification of novel therapies is urgently needed. Here, we establish a human PDAC organoid biobank from 31 genetically distinct lines, covering a representative range of tumor subtypes, and demonstrate that these reflect the molecular and phenotypic heterogeneity of primary PDAC tissue. We use CRISPR-Cas9 genome editing and drug screening to characterize drug-gene interactions with
Language	English
Publishing date	2022-02-02
Publishing country	United States
Document type	Journal Article
ISSN	2666-979X
ISSN (online)	2666-979X
DOI	10.1016/j.xgen.2022.100095
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Article: Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding

Gkountela, Sofia / Castro-Giner, Francesc / Szczerba, Barbara Maria / Vetter, Marcus / Landin, Julia / Scherrer, Ramona / Krol, Ilona / Scheidmann, Manuel C / Beisel, Christian / Stirnimann, Christian U / Kurzeder, Christian / Heinzelmann-Schwarz, Viola / Rochlitz, Christoph / Weber, Walter Paul / Aceto, Nicola

Cell. 2019 Jan. 10, v. 176, no. 1-2

2019

Abstract: The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single ...

Abstract	The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na+/K+ ATPase inhibitors that enable the dissociation of CTC clusters into single cells, leading to DNA methylation remodeling at critical sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compounds to suppress the spread of cancer.
Keywords	DNA methylation ; animal models ; binding sites ; breast neoplasms ; dissociation ; embryonic stem cells ; enzyme inhibitors ; metastasis ; neoplasm cells ; patients ; sodium-potassium-exchanging ATPase ; transcription factors
Language	English
Dates of publication	2019-0110
Size	p. 98-112.e14.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2018.11.046
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Article: WD40 proteins propel cellular networks.

Stirnimann, Christian U / Petsalaki, Evangelia / Russell, Robert B / Müller, Christoph W

Trends in biochemical sciences

2010 Volume 35, Issue 10, Page(s) 565–574

Abstract: Recent findings indicate that WD40 domains play central roles in biological processes by acting as hubs in cellular networks; however, they have been studied less intensely than other common domains, such as the kinase, PDZ or SH3 domains. As suggested ... ...

Abstract	Recent findings indicate that WD40 domains play central roles in biological processes by acting as hubs in cellular networks; however, they have been studied less intensely than other common domains, such as the kinase, PDZ or SH3 domains. As suggested by various interactome studies, they are among the most promiscuous interactors. Structural studies suggest that this property stems from their ability, as scaffolds, to interact with diverse proteins, peptides or nucleic acids using multiple surfaces or modes of interaction. A general scaffolding role is supported by the fact that no WD40 domain has been found with intrinsic enzymatic activity despite often being part of large molecular machines. We discuss the WD40 domain distributions in protein networks and structures of WD40-containing assemblies to demonstrate their versatility in mediating critical cellular functions.
MeSH term(s)	Animals ; DNA Damage ; Humans ; Protein Binding ; Proteins/chemistry ; Proteins/metabolism ; Repetitive Sequences, Amino Acid
Chemical Substances	Proteins
Language	English
Publishing date	2010-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	194216-5
ISSN	1362-4326 ; 0968-0004 ; 0376-5067
ISSN (online)	1362-4326
ISSN	0968-0004 ; 0376-5067
DOI	10.1016/j.tibs.2010.04.003
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Article ; Online: Structural basis of TBX5-DNA recognition: the T-box domain in its DNA-bound and -unbound form.

Stirnimann, Christian U / Ptchelkine, Denis / Grimm, Clemens / Müller, Christoph W

Journal of molecular biology

2010 Volume 400, Issue 1, Page(s) 71–81

Abstract: TBX5, a member of the T-box transcription factor family, plays an important role in heart and limb development. More than 60 single point or deletion mutations of human TBX5 are associated with Holt-Oram syndrome that manifests itself as heart and limb ... ...

Abstract	TBX5, a member of the T-box transcription factor family, plays an important role in heart and limb development. More than 60 single point or deletion mutations of human TBX5 are associated with Holt-Oram syndrome that manifests itself as heart and limb malformations in 1 out of 100,000 live births. The majority of these mutations are located in the TBX5 T-box domain. We solved the crystal structures of the human TBX5 T-box domain in its DNA-unbound form and in complex with a natural DNA target site allowing for the first time the comparison between unbound and DNA-bound forms. Our analysis identifies a 3(10)-helix at the C-terminus of the T-box domain as an inducible recognition element, critically required for the interaction with DNA, as it only forms upon DNA binding and is unstructured in the DNA-unbound form. Using circular dichroism, we characterized the thermal stability of six TBX5 mutants containing single point mutations in the T-box domain (M74V, G80R, W121G, G169R, T223M, and R237W) and compared them with wild-type protein. Mutants G80R and W121G show drastically reduced thermal stability, while the other mutants only show a marginal stability decrease. For all TBX5 mutants, binding affinities to specific and nonspecific DNA sequences were determined using isothermal titration calorimetry. All TBX5 mutants show reduced binding affinities to a specific DNA target site, although to various degrees. Interestingly, all tested TBX5 mutants differ in their ability to bind unspecific DNA, indicating that both sequence-specific and unspecific binding might contribute to the misregulation of target gene expression.
MeSH term(s)	Abnormalities, Multiple/genetics ; Abnormalities, Multiple/metabolism ; Amino Acid Sequence ; Animals ; Base Sequence ; Circular Dichroism ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; Fetal Proteins/chemistry ; Fetal Proteins/genetics ; Fetal Proteins/metabolism ; Heart Defects, Congenital/genetics ; Heart Defects, Congenital/metabolism ; Humans ; Limb Deformities, Congenital/genetics ; Limb Deformities, Congenital/metabolism ; Models, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Point Mutation ; Protein Structure, Tertiary ; Sequence Alignment ; T-Box Domain Proteins/chemistry ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism
Chemical Substances	Brachyury protein ; Fetal Proteins ; T-Box Domain Proteins ; T-box transcription factor 5 ; DNA (9007-49-2)
Language	English
Publishing date	2010-07-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2010.04.052
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Article ; Online: Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding.

Cell

2019 Volume 176, Issue 1-2, Page(s) 98–112.e14

Abstract	The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na
MeSH term(s)	Animals ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Differentiation ; Cell Line, Tumor ; Cell Proliferation ; DNA Methylation/physiology ; Disease Models, Animal ; Female ; Humans ; Mice ; Mice, Inbred NOD ; Nanog Homeobox Protein/metabolism ; Neoplasm Metastasis/genetics ; Neoplasm Metastasis/physiopathology ; Neoplastic Cells, Circulating/metabolism ; Neoplastic Cells, Circulating/pathology ; Octamer Transcription Factor-3/metabolism ; Repressor Proteins/metabolism ; SOXB1 Transcription Factors/metabolism ; Sin3 Histone Deacetylase and Corepressor Complex
Chemical Substances	NANOG protein, human ; Nanog Homeobox Protein ; Octamer Transcription Factor-3 ; POU5F1 protein, human ; Repressor Proteins ; SIN3A transcription factor ; SOX2 protein, human ; SOXB1 Transcription Factors ; Sin3 Histone Deacetylase and Corepressor Complex (EC 3.5.1.98)
Language	English
Publishing date	2019-06-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2018.11.046
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Article ; Online: Patient-derived xenografts and organoids model therapy response in prostate cancer.

Karkampouna, Sofia / La Manna, Federico / Benjak, Andrej / Kiener, Mirjam / De Menna, Marta / Zoni, Eugenio / Grosjean, Joël / Klima, Irena / Garofoli, Andrea / Bolis, Marco / Vallerga, Arianna / Theurillat, Jean-Philippe / De Filippo, Maria R / Genitsch, Vera / Keller, David / Booij, Tijmen H / Stirnimann, Christian U / Eng, Kenneth / Sboner, Andrea /

Ng, Charlotte K Y / Piscuoglio, Salvatore / Gray, Peter C / Spahn, Martin / Rubin, Mark A / Thalmann, George N / Kruithof-de Julio, Marianna

Nature communications

2021 Volume 12, Issue 1, Page(s) 1117

Abstract: Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment- ... ...

Abstract	Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.
MeSH term(s)	Androgens/metabolism ; Antineoplastic Agents/therapeutic use ; Genome, Human ; Humans ; Male ; Models, Biological ; Mutation/genetics ; Neoplasm Metastasis ; Organoids/pathology ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/therapy ; Transcriptome/genetics ; Xenograft Model Antitumor Assays
Chemical Substances	Androgens ; Antineoplastic Agents
Language	English
Publishing date	2021-02-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-21300-6
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Article ; Online: Structural basis for the oligomerization-state switch from a dimer to a trimer of an engineered cortexillin-1 coiled-coil variant.

Bjelić, Saša / Wieser, Mara / Frey, Daniel / Stirnimann, Christian U / Chance, Mark R / Jaussi, Rolf / Steinmetz, Michel O / Kammerer, Richard A

PloS one

2013 Volume 8, Issue 5, Page(s) e63370

Abstract: Coiled coils are well suited to drive subunit oligomerization and are widely used in applications ranging from basic research to medicine. The optimization of these applications requires a detailed understanding of the molecular determinants that control ...

Abstract	Coiled coils are well suited to drive subunit oligomerization and are widely used in applications ranging from basic research to medicine. The optimization of these applications requires a detailed understanding of the molecular determinants that control of coiled-coil formation. Although many of these determinants have been identified and characterized in great detail, a puzzling observation is that their presence does not necessarily correlate with the oligomerization state of a given coiled-coil structure. Thus, other determinants must play a key role. To address this issue, we recently investigated the unrelated coiled-coil domains from GCN4, ATF1 and cortexillin-1 as model systems. We found that well-known trimer-specific oligomerization-state determinants, such as the distribution of isoleucine residues at heptad-repeat core positions or the trimerization motif Arg-h-x-x-h-Glu (where h = hydrophobic amino acid; x = any amino acid), switch the peptide's topology from a dimer to a trimer only when inserted into the trigger sequence, a site indispensable for coiled-coil formation. Because high-resolution structural information could not be obtained for the full-length, three-stranded cortexillin-1 coiled coil, we here report the detailed biophysical and structural characterization of a shorter variant spanning the trigger sequence using circular dichroism, anatytical ultracentrifugation and x-ray crystallography. We show that the peptide forms a stable α-helical trimer in solution. We further determined the crystal structure of an optimised variant at a resolution of 1.65 Å, revealing that the peptide folds into a parallel, three-stranded coiled coil. The two complemented R-IxxIE trimerization motifs and the additional hydrophobic core isoleucine residue adopt the conformations seen in other extensively characterized parallel, three-stranded coiled coils. These findings not only confirm the structural basis for the switch in oligomerization state from a dimer to a trimer observed for the full-length cortexillin-1 coiled-coil domain, but also provide further evidence for a general link between oligomerization-state specificity and trigger-sequence function.
MeSH term(s)	Amino Acid Sequence ; Microfilament Proteins/chemistry ; Models, Molecular ; Molecular Sequence Data ; Protein Engineering ; Protein Multimerization ; Protein Stability ; Protein Structure, Quaternary ; Protein Structure, Secondary
Chemical Substances	Microfilament Proteins
Language	English
Publishing date	2013-05-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0063370
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Article ; Online: Chromatin-modifying complex component Nurf55/p55 associates with histones H3 and H4 and polycomb repressive complex 2 subunit Su(z)12 through partially overlapping binding sites.

Nowak, Agnieszka J / Alfieri, Claudio / Stirnimann, Christian U / Rybin, Vladimir / Baudin, Florence / Ly-Hartig, Nga / Lindner, Doris / Müller, Christoph W

The Journal of biological chemistry

2011 Volume 286, Issue 26, Page(s) 23388–23396

Abstract: Drosophila Nurf55 is a component of different chromatin-modifying complexes, including the PRC2 (Polycomb repressive complex 2). Based on the 1.75-Å crystal structure of Nurf55 bound to histone H4 helix 1, we analyzed interactions of Nurf55 (Nurf55 or ... ...

Abstract	Drosophila Nurf55 is a component of different chromatin-modifying complexes, including the PRC2 (Polycomb repressive complex 2). Based on the 1.75-Å crystal structure of Nurf55 bound to histone H4 helix 1, we analyzed interactions of Nurf55 (Nurf55 or p55 in fly and RbAp48/46 in human) with the N-terminal tail of histone H3, the first helix of histone H4, and an N-terminal fragment of the PRC2 subunit Su(z)12 using isothermal calorimetry and pulldown experiments. Site-directed mutagenesis identified the binding site of histone H3 at the top of the Nurf55 WD40 propeller. Unmodified or K9me3- or K27me3-containing H3 peptides were bound with similar affinities, whereas the affinity for K4me3-containing H3 peptides was reduced. Helix 1 of histone H4 and Su(z)12 bound to the edge of the β-propeller using overlapping binding sites. Our results show similarities in the recognition of histone H4 and Su(z)12 and identify Nurf55 as a versatile interactor that simultaneously contacts multiple partners.
MeSH term(s)	Animals ; Binding Sites ; Crystallography, X-Ray ; Drosophila Proteins/chemistry ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster ; Histone-Lysine N-Methyltransferase/chemistry ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/chemistry ; Histones/genetics ; Histones/metabolism ; Polycomb Repressive Complex 2 ; Polycomb-Group Proteins ; Protein Structure, Secondary ; Repressor Proteins/chemistry ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Retinoblastoma-Binding Protein 4/chemistry ; Retinoblastoma-Binding Protein 4/genetics ; Retinoblastoma-Binding Protein 4/metabolism
Chemical Substances	Caf1-55 protein, Drosophila ; Drosophila Proteins ; Histones ; Polycomb-Group Proteins ; Repressor Proteins ; Retinoblastoma-Binding Protein 4 ; Su(z)12 protein, Drosophila ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Polycomb Repressive Complex 2 (EC 2.1.1.43)
Language	English
Publishing date	2011-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M110.207407
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Article ; Online: Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis.

Luna-Zurita, Luis / Stirnimann, Christian U / Glatt, Sebastian / Kaynak, Bogac L / Thomas, Sean / Baudin, Florence / Samee, Md Abul Hassan / He, Daniel / Small, Eric M / Mileikovsky, Maria / Nagy, Andras / Holloway, Alisha K / Pollard, Katherine S / Müller, Christoph W / Bruneau, Benoit G

Cell

2016 Volume 164, Issue 5, Page(s) 999–1014

Abstract: Transcription factors (TFs) are thought to function with partners to achieve specificity and precise quantitative outputs. In the developing heart, heterotypic TF interactions, such as between the T-box TF TBX5 and the homeodomain TF NKX2-5, have been ... ...

Abstract	Transcription factors (TFs) are thought to function with partners to achieve specificity and precise quantitative outputs. In the developing heart, heterotypic TF interactions, such as between the T-box TF TBX5 and the homeodomain TF NKX2-5, have been proposed as a mechanism for human congenital heart defects. We report extensive and complex interdependent genomic occupancy of TBX5, NKX2-5, and the zinc finger TF GATA4 coordinately controlling cardiac gene expression, differentiation, and morphogenesis. Interdependent binding serves not only to co-regulate gene expression but also to prevent TFs from distributing to ectopic loci and activate lineage-inappropriate genes. We define preferential motif arrangements for TBX5 and NKX2-5 cooperative binding sites, supported at the atomic level by their co-crystal structure bound to DNA, revealing a direct interaction between the two factors and induced DNA bending. Complex interdependent binding mechanisms reveal tightly regulated TF genomic distribution and define a combinatorial logic for heterotypic TF regulation of differentiation.
MeSH term(s)	Animals ; Cell Differentiation ; Crystallography, X-Ray ; Embryo, Mammalian/metabolism ; GATA4 Transcription Factor/metabolism ; Homeobox Protein Nkx-2.5 ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Mice ; Mice, Transgenic ; Models, Molecular ; Myocardium/cytology ; Myocardium/metabolism ; Organogenesis ; Promoter Regions, Genetic ; Protein Interaction Domains and Motifs ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	GATA4 Transcription Factor ; Gata4 protein, mouse ; Homeobox Protein Nkx-2.5 ; Homeodomain Proteins ; Nkx2-5 protein, mouse ; T-Box Domain Protein 2 ; T-Box Domain Proteins ; Transcription Factors
Language	English
Publishing date	2016-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2016.01.004
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Article ; Online: A type IV translocated Legionella cysteine phytase counteracts intracellular growth restriction by phytate.

Weber, Stephen / Stirnimann, Christian U / Wieser, Mara / Frey, Daniel / Meier, Roger / Engelhardt, Sabrina / Li, Xiaodan / Capitani, Guido / Kammerer, Richard A / Hilbi, Hubert

The Journal of biological chemistry

2014 Volume 289, Issue 49, Page(s) 34175–34188

Abstract: The causative agent of Legionnaires' pneumonia, Legionella pneumophila, colonizes diverse environmental niches, including biofilms, plant material, and protozoa. In these habitats, myo-inositol hexakisphosphate (phytate) is prevalent and used as a ... ...

Abstract	The causative agent of Legionnaires' pneumonia, Legionella pneumophila, colonizes diverse environmental niches, including biofilms, plant material, and protozoa. In these habitats, myo-inositol hexakisphosphate (phytate) is prevalent and used as a phosphate storage compound or as a siderophore. L. pneumophila replicates in protozoa and mammalian phagocytes within a unique "Legionella-containing vacuole." The bacteria govern host cell interactions through the Icm/Dot type IV secretion system (T4SS) and ∼300 different "effector" proteins. Here we characterize a hitherto unrecognized Icm/Dot substrate, LppA, as a phytate phosphatase (phytase). Phytase activity of recombinant LppA required catalytically essential cysteine (Cys(231)) and arginine (Arg(237)) residues. The structure of LppA at 1.4 Å resolution revealed a mainly α-helical globular protein stabilized by four antiparallel β-sheets that binds two phosphate moieties. The phosphates localize to a P-loop active site characteristic of dual specificity phosphatases or to a non-catalytic site, respectively. Phytate reversibly abolished growth of L. pneumophila in broth, and growth inhibition was relieved by overproduction of LppA or by metal ion titration. L. pneumophila lacking lppA replicated less efficiently in phytate-loaded Acanthamoeba castellanii or Dictyostelium discoideum, and the intracellular growth defect was complemented by the phytase gene. These findings identify the chelator phytate as an intracellular bacteriostatic component of cell-autonomous host immunity and reveal a T4SS-translocated L. pneumophila phytase that counteracts intracellular bacterial growth restriction by phytate. Thus, bacterial phytases might represent therapeutic targets to combat intracellular pathogens.
MeSH term(s)	6-Phytase/chemistry ; 6-Phytase/genetics ; 6-Phytase/metabolism ; Acanthamoeba castellanii/metabolism ; Acanthamoeba castellanii/microbiology ; Arginine/chemistry ; Arginine/metabolism ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Bacterial Secretion Systems/genetics ; Catalytic Domain ; Cysteine/chemistry ; Cysteine/metabolism ; Dictyostelium/metabolism ; Dictyostelium/microbiology ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Gene Expression ; Genetic Complementation Test ; Host-Pathogen Interactions ; Kinetics ; Legionella pneumophila/drug effects ; Legionella pneumophila/enzymology ; Legionella pneumophila/genetics ; Phytic Acid/chemistry ; Phytic Acid/metabolism ; Phytic Acid/pharmacology ; Protein Structure, Secondary ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
Chemical Substances	Bacterial Proteins ; Bacterial Secretion Systems ; Recombinant Proteins ; Phytic Acid (7IGF0S7R8I) ; Arginine (94ZLA3W45F) ; 6-Phytase (EC 3.1.3.26) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2014-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M114.592568
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