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Article ; Online: Mechanistic insights into the aggregation pathway of the patient-derived immunoglobulin light chain variable domain protein FOR005.

Pradhan, Tejaswini / Sarkar, Riddhiman / Meighen-Berger, Kevin M / Feige, Matthias J / Zacharias, Martin / Reif, Bernd

2023 Volume 14, Issue 1, Page(s) 3755

Abstract: Systemic antibody light chain (AL) amyloidosis is characterized by deposition of amyloid fibrils. Prior to fibril formation, soluble oligomeric AL protein has a direct cytotoxic effect on cardiomyocytes. We focus on the patient derived λ-III AL variable ... ...

Abstract	Systemic antibody light chain (AL) amyloidosis is characterized by deposition of amyloid fibrils. Prior to fibril formation, soluble oligomeric AL protein has a direct cytotoxic effect on cardiomyocytes. We focus on the patient derived λ-III AL variable domain FOR005 which is mutated at five positions with respect to the closest germline protein. Using solution-state NMR spectroscopy, we follow the individual steps involved in protein misfolding from the native to the amyloid fibril state. Unfavorable mutations in the complementary determining regions introduce a strain in the native protein structure which yields partial unfolding. Driven by electrostatic interactions, the protein converts into a high molecular weight, oligomeric, molten globule. The high local concentration of aggregation prone regions in the oligomer finally catalyzes the conversion into fibrils. The topology is determined by balanced electrostatic interactions in the fibril core implying a 180° rotational switch of the beta-sheets around the conserved disulfide bond.
MeSH term(s)	Humans ; Immunoglobulin Light Chains/chemistry ; Amyloidosis/metabolism ; Immunoglobulin Light-chain Amyloidosis/metabolism ; Amyloid/metabolism ; Mutation
Chemical Substances	Immunoglobulin Light Chains ; Amyloid
Language	English
Publishing date	2023-06-23
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/s41467-023-39280-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: A chemical probe unravels the reactive proteome of health-associated catechols.

Weigert Muñoz, Angela / Meighen-Berger, Kevin M / Hacker, Stephan M / Feige, Matthias J / Sieber, Stephan A

Chemical science

2023 Volume 14, Issue 32, Page(s) 8635–8643

Abstract: Catechol-containing natural products are common constituents of foods, drinks, and drugs. Natural products carrying this motif are often associated with beneficial biological effects such as anticancer activity and neuroprotection. However, the molecular ...

Abstract	Catechol-containing natural products are common constituents of foods, drinks, and drugs. Natural products carrying this motif are often associated with beneficial biological effects such as anticancer activity and neuroprotection. However, the molecular mode of action behind these properties is poorly understood. Here, we apply a mass spectrometry-based competitive chemical proteomics approach to elucidate the target scope of catechol-containing bioactive molecules from diverse foods and drugs. Inspired by the protein reactivity of catecholamine neurotransmitters, we designed and synthesised a broadly reactive minimalist catechol chemical probe based on dopamine. Initial labelling experiments in live human cells demonstrated broad protein binding by the probe, which was largely outcompeted by its parent compound dopamine. Next, we investigated the competition profile of a selection of biologically relevant catechol-containing substances. With this approach, we characterised the protein reactivity and the target scope of dopamine and ten biologically relevant catechols. Strikingly, proteins associated with the endoplasmic reticulum (ER) were among the main targets. ER stress assays in the presence of reactive catechols revealed an activation of the unfolded protein response (UPR). The UPR is highly relevant in oncology and cellular resilience, which may provide an explanation of the health-promoting effects attributed to many catechol-containing natural products.
Language	English
Publishing date	2023-07-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/d3sc00888f
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Article ; Online: Intramembrane client recognition potentiates the chaperone functions of calnexin.

Bloemeke, Nicolas / Meighen-Berger, Kevin / Hitzenberger, Manuel / Bach, Nina C / Parr, Marina / Coelho, Joao Pl / Frishman, Dmitrij / Zacharias, Martin / Sieber, Stephan A / Feige, Matthias J

The EMBO journal

2022 , Page(s) e110959

Abstract: One-third of the human proteome is comprised of membrane proteins, which are particularly vulnerable to misfolding and often require folding assistance by molecular chaperones. Calnexin (CNX), which engages client proteins via its sugar-binding lectin ... ...

Abstract	One-third of the human proteome is comprised of membrane proteins, which are particularly vulnerable to misfolding and often require folding assistance by molecular chaperones. Calnexin (CNX), which engages client proteins via its sugar-binding lectin domain, is one of the most abundant ER chaperones, and plays an important role in membrane protein biogenesis. Based on mass spectrometric analyses, we here show that calnexin interacts with a large number of nonglycosylated membrane proteins, indicative of additional nonlectin binding modes. We find that calnexin preferentially bind misfolded membrane proteins and that it uses its single transmembrane domain (TMD) for client recognition. Combining experimental and computational approaches, we systematically dissect signatures for intramembrane client recognition by calnexin, and identify sequence motifs within the calnexin TMD region that mediate client binding. Building on this, we show that intramembrane client binding potentiates the chaperone functions of calnexin. Together, these data reveal a widespread role of calnexin client recognition in the lipid bilayer, which synergizes with its established lectin-based substrate binding. Molecular chaperones thus can combine different interaction modes to support the biogenesis of the diverse eukaryotic membrane proteome.
Language	English
Publishing date	2022-10-31
Publishing country	England
Document type	Journal Article
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.2022110959
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Article ; Online: A network of chaperones prevents and detects failures in membrane protein lipid bilayer integration.

Coelho, João P L / Stahl, Matthias / Bloemeke, Nicolas / Meighen-Berger, Kevin / Alvira, Carlos Piedrafita / Zhang, Zai-Rong / Sieber, Stephan A / Feige, Matthias J

Nature communications

2019 Volume 10, Issue 1, Page(s) 672

Abstract: A fundamental step in membrane protein biogenesis is their integration into the lipid bilayer with a defined orientation of each transmembrane segment. Despite this, it remains unclear how cells detect and handle failures in this process. Here we show ... ...

Abstract	A fundamental step in membrane protein biogenesis is their integration into the lipid bilayer with a defined orientation of each transmembrane segment. Despite this, it remains unclear how cells detect and handle failures in this process. Here we show that single point mutations in the membrane protein connexin 32 (Cx32), which cause Charcot-Marie-Tooth disease, can cause failures in membrane integration. This leads to Cx32 transport defects and rapid degradation. Our data show that multiple chaperones detect and remedy this aberrant behavior: the ER-membrane complex (EMC) aids in membrane integration of low-hydrophobicity transmembrane segments. If they fail to integrate, these are recognized by the ER-lumenal chaperone BiP. Ultimately, the E3 ligase gp78 ubiquitinates Cx32 proteins, targeting them for degradation. Thus, cells use a coordinated system of chaperones for the complex task of membrane protein biogenesis, which can be compromised by single point mutations, causing human disease.
MeSH term(s)	Animals ; COS Cells ; Charcot-Marie-Tooth Disease/genetics ; Charcot-Marie-Tooth Disease/metabolism ; Chlorocebus aethiops ; Connexins/genetics ; Connexins/metabolism ; Endoplasmic Reticulum/genetics ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Chaperone BiP ; Gap Junctions/metabolism ; HEK293 Cells ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Humans ; Lipid Bilayers/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; Mutation ; Gap Junction beta-1 Protein
Chemical Substances	Connexins ; Endoplasmic Reticulum Chaperone BiP ; Heat-Shock Proteins ; Lipid Bilayers ; Membrane Proteins ; Molecular Chaperones
Language	English
Publishing date	2019-02-08
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/s41467-019-08632-0
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Article ; Online: Publisher Correction: A network of chaperones prevents and detects failures in membrane protein lipid bilayer integration.

Coelho, João P L / Stahl, Matthias / Bloemeke, Nicolas / Meighen-Berger, Kevin / Alvira, Carlos Piedrafita / Zhang, Zai-Rong / Sieber, Stephan A / Feige, Matthias J

Nature communications

2019 Volume 10, Issue 1, Page(s) 1908

Abstract: The original version of this Article contained errors in Fig. 1 and Supplementary Fig. 3. In Fig. 1, the labels indicating the ... ...

Abstract	The original version of this Article contained errors in Fig. 1 and Supplementary Fig. 3. In Fig. 1, the labels indicating the Cx32
Language	English
Publishing date	2019-04-18
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-09912-5
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Article ; Online: Fluorescent palladium(II) and platinum(II) NHC/1,2,3-triazole complexes: antiproliferative activity and selectivity against cancer cells.

Schlagintweit, Jonas F / Jakob, Christian H G / Meighen-Berger, Kevin / Gronauer, Thomas F / Weigert Muñoz, Angela / Weiß, Vanessa / Feige, Matthias J / Sieber, Stephan A / Correia, João D G / Kühn, Fritz E

Dalton transactions (Cambridge, England : 2003)

2021 Volume 50, Issue 6, Page(s) 2158–2166

Abstract: Fluorescent Pd(ii) and Pt(ii) complexes bearing 4-methylene-7-methoxycoumarin (MMC) and 2,6-diispropylphenyl (Dipp) substituted NHC/1,2,3-triazole hybrid ligands are described. Depending on the reaction conditions two different ligand coordination modes ... ...

Abstract	Fluorescent Pd(ii) and Pt(ii) complexes bearing 4-methylene-7-methoxycoumarin (MMC) and 2,6-diispropylphenyl (Dipp) substituted NHC/1,2,3-triazole hybrid ligands are described. Depending on the reaction conditions two different ligand coordination modes are observed, i.e., bidentate solely coordinating via NHCs or tetradentate coordinating via NHCs and 1,2,3-triazoles. All Dipp substituted complexes show antiproliferative activity against cervix (HeLa) and breast (MCF-7) human carcinoma cells. The activity significantly depends on the coordination mode, with the tetradentate motif being notably more effective (HeLa: IC50 = 3.9 μM to 4.7 μM; MCF-7: IC50 = 2.07 μM to 2.35 μM). Amongst the MMC series, only the Pd(ii) complex featuring the bidentate coordination mode is active against HeLa (IC50 = 6.1 μM). In contrast to its structurally related Dipp derivative (SI = 0.6), it shows a high selectivity for HeLa (SI > 16) compared to healthy skin cells (HaCaT). According to fluorescence microscopy, this compound is presumably located in late endosomes or lysosomes.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Coordination Complexes/chemistry ; Coordination Complexes/pharmacology ; Coumarins/chemistry ; Coumarins/pharmacology ; Fluorescence ; Humans ; Microscopy, Fluorescence ; Neoplasms/drug therapy ; Organometallic Compounds/chemistry ; Organometallic Compounds/pharmacology ; Palladium/chemistry ; Palladium/pharmacology ; Platinum/chemistry ; Platinum/pharmacology ; Triazoles/chemistry ; Triazoles/pharmacology
Chemical Substances	Antineoplastic Agents ; Coordination Complexes ; Coumarins ; Organometallic Compounds ; Triazoles ; Platinum (49DFR088MY) ; Palladium (5TWQ1V240M)
Language	English
Publishing date	2021-01-25
Publishing country	England
Document type	Journal Article
ZDB-ID	1472887-4
ISSN	1477-9234 ; 1364-5447 ; 0300-9246 ; 1477-9226
ISSN (online)	1477-9234 ; 1364-5447
ISSN	0300-9246 ; 1477-9226
DOI	10.1039/d0dt04114a
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Article ; Online: Differential Substrate Usage and Metabolic Fluxes in

Chen, Fan / Rydzewski, Kerstin / Kutzner, Erika / Häuslein, Ina / Schunder, Eva / Wang, Xinzhe / Meighen-Berger, Kevin / Grunow, Roland / Eisenreich, Wolfgang / Heuner, Klaus

Frontiers in cellular and infection microbiology

2017 Volume 7, Page(s) 275

Abstract: Francisella ... ...

Abstract	Francisella tularensis
Language	English
Publishing date	2017
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2017.00275
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Article ; Online: Differential Substrate Usage and Metabolic Fluxes in Francisella tularensis Subspecies holarctica and Francisella novicida

Chen, Fan / Rydzewski, Kerstin / Kutzner, Erika / Häuslein, Ina / Schunder, Eva / Wang, Xinzhe / Meighen-Berger, Kevin / Grunow, Roland / Eisenreich, Wolfgang / Heuner, Klaus

2017

Abstract: Francisella tularensis is an intracellular pathogen for many animals causing the infectious disease, tularemia. Whereas F. tularensis subsp. holarctica is highly pathogenic for humans, F. novicida is almost avirulent for humans, but virulent for mice. In ...

Abstract	Francisella tularensis is an intracellular pathogen for many animals causing the infectious disease, tularemia. Whereas F. tularensis subsp. holarctica is highly pathogenic for humans, F. novicida is almost avirulent for humans, but virulent for mice. In order to compare metabolic fluxes between these strains, we performed 13C-labeling experiments with F. tularensis subsp. holarctica wild type (beaver isolate), F. tularensis subsp. holarctica strain LVS, or F. novicida strain U112 in complex media containing either [U-13C6]glucose, [1,2-13C2]glucose, [U-13C3]serine, or [U-13C3]glycerol. GC/MS-based isotopolog profiling of amino acids, polysaccharide-derived glucose, free fructose, amino sugars derived from the cell wall, fatty acids, 3-hydroxybutyrate, lactate, succinate and malate revealed uptake and metabolic usage of all tracers under the experimental conditions with glucose being the major carbon source for all strains under study. The labeling patterns of the F. tularensis subsp. holarctica wild type were highly similar to those of the LVS strain, but showed remarkable differences to the labeling profiles of the metabolites from the F. novicida strain. Glucose was directly used for polysaccharide and cell wall biosynthesis with higher rates in F. tularensis subsp. holarctica or metabolized, with higher rates in F. novicida, via glycolysis and the non-oxidative pentose phosphate pathway (PPP). Catabolic turnover of glucose via gluconeogenesis was also observed. In all strains, Ala was mainly synthesized from pyruvate, although no pathway from pyruvate to Ala is annotated in the genomes of F. tularensis and F. novicida. Glycerol efficiently served as a gluconeogenetic substrate in F. novicida, but only less in the F. tularensis subsp. holarctica strains. In any of the studied strains, serine did not serve as a major substrate and was not significantly used for gluconeogenesis under the experimental conditions. Rather, it was only utilized, at low rates, in downstream metabolic processes, e.g., via acetyl-CoA ...
Keywords	610 Medizin ; ddc:610
Subject code	570
Language	English
Publishing date	2017-06-21
Publisher	Robert Koch-Institut, Epidemiologie und Gesundheitsberichterstattung
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Differential Substrate Usage and Metabolic Fluxes in Francisella tularensis Subspecies holarctica and Francisella novicida

Chen, Fan / Rydzewski, Kerstin / Kutzner, Erika / Häuslein, Ina / Schunder, Eva / Wang, Xinzhe / Meighen-Berger, Kevin / Grunow, Roland / Eisenreich, Wolfgang / Heuner, Klaus

2017

Abstract	Francisella tularensis is an intracellular pathogen for many animals causing the infectious disease, tularemia. Whereas F. tularensis subsp. holarctica is highly pathogenic for humans, F. novicida is almost avirulent for humans, but virulent for mice. In order to compare metabolic fluxes between these strains, we performed 13C-labeling experiments with F. tularensis subsp. holarctica wild type (beaver isolate), F. tularensis subsp. holarctica strain LVS, or F. novicida strain U112 in complex media containing either [U-13C6]glucose, [1,2-13C2]glucose, [U-13C3]serine, or [U-13C3]glycerol. GC/MS-based isotopolog profiling of amino acids, polysaccharide-derived glucose, free fructose, amino sugars derived from the cell wall, fatty acids, 3-hydroxybutyrate, lactate, succinate and malate revealed uptake and metabolic usage of all tracers under the experimental conditions with glucose being the major carbon source for all strains under study. The labeling patterns of the F. tularensis subsp. holarctica wild type were highly similar to those of the LVS strain, but showed remarkable differences to the labeling profiles of the metabolites from the F. novicida strain. Glucose was directly used for polysaccharide and cell wall biosynthesis with higher rates in F. tularensis subsp. holarctica or metabolized, with higher rates in F. novicida, via glycolysis and the non-oxidative pentose phosphate pathway (PPP). Catabolic turnover of glucose via gluconeogenesis was also observed. In all strains, Ala was mainly synthesized from pyruvate, although no pathway from pyruvate to Ala is annotated in the genomes of F. tularensis and F. novicida. Glycerol efficiently served as a gluconeogenetic substrate in F. novicida, but only less in the F. tularensis subsp. holarctica strains. In any of the studied strains, serine did not serve as a major substrate and was not significantly used for gluconeogenesis under the experimental conditions. Rather, it was only utilized, at low rates, in downstream metabolic processes, e.g., via acetyl-CoA in the citrate cycle and for fatty acid biosynthesis, especially in the F. tularensis subsp. holarctica strains. In summary, the data reflect differential metabolite fluxes in F. tularensis subsp. holarctica and F. novicida suggesting that the different utilization of substrates could be related to host specificity and virulence of Francisella.
Keywords	Medizin ; ddc:610
Subject code	570
Language	English
Publishing date	2017-06-21
Publisher	Epidemiologie und Gesundheitsberichterstattung
Publishing country	de
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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