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  1. Article ; Online: A viral insulin-like peptide inhibits IGF-1 receptor phosphorylation and regulates IGF1R gene expression.

    Chrudinová, Martina / Kirk, Nicholas S / Chuard, Aurelien / Venugopal, Hari / Zhang, Fa / Lubos, Marta / Gelfanov, Vasily / Páníková, Terezie / Žáková, Lenka / Cutone, Julianne / Mojares, Matthew / DiMarchi, Richard / Jiráček, Jiří / Altindis, Emrah

    Molecular metabolism

    2024  Volume 80, Page(s) 101863

    Abstract: Objective: The insulin/IGF superfamily is conserved across vertebrates and invertebrates. Our team has identified five viruses containing genes encoding viral insulin/IGF-1 like peptides (VILPs) closely resembling human insulin and IGF-1. This study ... ...

    Abstract Objective: The insulin/IGF superfamily is conserved across vertebrates and invertebrates. Our team has identified five viruses containing genes encoding viral insulin/IGF-1 like peptides (VILPs) closely resembling human insulin and IGF-1. This study aims to characterize the impact of Mandarin fish ranavirus (MFRV) and Lymphocystis disease virus-Sa (LCDV-Sa) VILPs on the insulin/IGF system for the first time.
    Methods: We chemically synthesized single chain (sc, IGF-1 like) and double chain (dc, insulin like) forms of MFRV and LCDV-Sa VILPs. Using cell lines overexpressing either human insulin receptor isoform A (IR-A), isoform B (IR-B) or IGF-1 receptor (IGF1R), and AML12 murine hepatocytes, we characterized receptor binding, insulin/IGF signaling. We further characterized the VILPs' effects of proliferation and IGF1R and IR gene expression, and compared them to native ligands. Additionally, we performed insulin tolerance test in CB57BL/6 J mice to examine in vivo effects of VILPs on blood glucose levels. Finally, we employed cryo-electron microscopy (cryoEM) to analyze the structure of scMFRV-VILP in complex with the IGF1R ectodomain.
    Results: VILPs can bind to human IR and IGF1R, stimulate receptor autophosphorylation and downstream signaling pathways. Notably, scMFRV-VILP exhibited a particularly strong affinity for IGF1R, with a mere 10-fold decrease compared to human IGF-1. At high concentrations, scMFRV-VILP selectively reduced IGF-1 stimulated IGF1R autophosphorylation and Erk phosphorylation (Ras/MAPK pathway), while leaving Akt phosphorylation (PI3K/Akt pathway) unaffected, indicating a potential biased inhibitory function. Prolonged exposure to MFRV-VILP led to a significant decrease in IGF1R gene expression in IGF1R overexpressing cells and AML12 hepatocytes. Furthermore, insulin tolerance test revealed scMFRV-VILP's sustained glucose-lowering effect compared to insulin and IGF-1. Finally, cryo-EM analysis revealed that scMFRV-VILP engages with IGF1R in a manner closely resembling IGF-1 binding, resulting in a highly analogous structure.
    Conclusions: This study introduces MFRV and LCDV-Sa VILPs as novel members of the insulin/IGF superfamily. Particularly, scMFRV-VILP exhibits a biased inhibitory effect on IGF1R signaling at high concentrations, selectively inhibiting IGF-1 stimulated IGF1R autophosphorylation and Erk phosphorylation, without affecting Akt phosphorylation. In addition, MFRV-VILP specifically regulates IGF-1R gene expression and IGF1R protein levels without affecting IR. CryoEM analysis confirms that scMFRV-VILP' binding to IGF1R is mirroring the interaction pattern observed with IGF-1. These findings offer valuable insights into IGF1R action and inhibition, suggesting potential applications in development of IGF1R specific inhibitors and advancing long-lasting insulins.
    MeSH term(s) Humans ; Animals ; Mice ; Receptor, IGF Type 1/genetics ; Receptor, IGF Type 1/metabolism ; Insulin-Like Growth Factor I/genetics ; Insulin-Like Growth Factor I/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Cryoelectron Microscopy ; Insulin/metabolism ; Protein Isoforms/metabolism ; Gene Expression
    Chemical Substances Receptor, IGF Type 1 (EC 2.7.10.1) ; Insulin-Like Growth Factor I (67763-96-6) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Insulin ; Protein Isoforms ; IGF1R protein, human
    Language English
    Publishing date 2024-01-03
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2708735-9
    ISSN 2212-8778 ; 2212-8778
    ISSN (online) 2212-8778
    ISSN 2212-8778
    DOI 10.1016/j.molmet.2023.101863
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Insulin Analogues with Altered Insulin Receptor Isoform Binding Specificities and Enhanced Aggregation Stabilities.

    Páníková, Terezie / Mitrová, Katarína / Halamová, Tereza / Mrzílková, Karolína / Pícha, Jan / Chrudinová, Martina / Kurochka, Andrii / Selicharová, Irena / Žáková, Lenka / Jiráček, Jiří

    Journal of medicinal chemistry

    2021  Volume 64, Issue 19, Page(s) 14848–14859

    Abstract: Insulin is a lifesaver for millions of diabetic patients. There is a need for new insulin analogues with more physiological profiles and analogues that will be thermally more stable than human insulin. Here, we describe the chemical engineering of 48 ... ...

    Abstract Insulin is a lifesaver for millions of diabetic patients. There is a need for new insulin analogues with more physiological profiles and analogues that will be thermally more stable than human insulin. Here, we describe the chemical engineering of 48 insulin analogues that were designed to have changed binding specificities toward isoforms A and B of the insulin receptor (IR-A and IR-B). We systematically modified insulin at the C-terminus of the B-chain, at the N-terminus of the A-chain, and at A14 and A18 positions. We discovered an insulin analogue that has Cα-carboxyamidated Glu at B31 and Ala at B29 and that has a more than 3-fold-enhanced binding specificity in favor of the "metabolic" IR-B isoform. The analogue is more resistant to the formation of insulin fibrils at 37 °C and is also more efficient in mice than human insulin. Therefore, [Ala
    MeSH term(s) Amino Acid Sequence ; Animals ; Antigens, CD/chemistry ; Antigens, CD/metabolism ; Calorimetry/methods ; Humans ; Insulin/analogs & derivatives ; Insulin/metabolism ; Insulin Resistance ; Male ; Mice, Inbred C57BL ; Phosphorylation ; Protein Aggregates ; Protein Binding ; Protein Isoforms/chemistry ; Protein Isoforms/metabolism ; Receptor, Insulin/chemistry ; Receptor, Insulin/metabolism ; Mice
    Chemical Substances Antigens, CD ; Insulin ; Protein Aggregates ; Protein Isoforms ; INSR protein, human (EC 2.7.10.1) ; Receptor, Insulin (EC 2.7.10.1)
    Language English
    Publishing date 2021-09-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.1c01388
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
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  3. Article ; Online: Characterization of viral insulins reveals white adipose tissue-specific effects in mice.

    Chrudinová, Martina / Moreau, François / Noh, Hye Lim / Páníková, Terezie / Žáková, Lenka / Friedline, Randall H / Valenzuela, Francisco A / Kim, Jason K / Jiráček, Jiří / Kahn, C Ronald / Altindis, Emrah

    Molecular metabolism

    2020  Volume 44, Page(s) 101121

    Abstract: Objective: Members of the insulin/insulin-like growth factor (IGF) superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human ...

    Abstract Objective: Members of the insulin/insulin-like growth factor (IGF) superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single-chain (sc), i.e., IGF-1-like, forms of the viral insulin/IGF-1-like peptides (VILPs), we previously showed that they can stimulate human receptors. Because these peptides possess potential cleavage sites to form double chain (dc), i.e., more insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1) for the first time.
    Methods: The dcVILPs were chemically synthesized. Using murine fibroblast cell lines overexpressing insulin receptor (IR-A or IR-B) or IGF1R, we first determined the binding affinity of dcVILPs to the receptors and characterized post-receptor signaling. Further, we used C57BL/6J mice to study the effect of dcVILPs on lowering blood glucose. We designed a 3-h dcVILP in vivo infusion experiment to determine the glucose uptake in different tissues.
    Results: GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A and IR-B) and to the IGF1R, and for the latter, show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75 nmol/kg/min) stimulated a comparable glucose uptake in heart and skeletal muscle and brown adipose tissue, GIV dcVILP stimulated 2-fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This was associated with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene expression compared to insulin in WAT.
    Conclusions: Our results show that GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action, design new analogs that specifically target the tissues and provide new insights into their potential role in disease.
    MeSH term(s) Adipose Tissue, Brown/metabolism ; Adipose Tissue, White/metabolism ; Animals ; Antigens, CD ; Cell Line ; Glucose/metabolism ; Humans ; Insulin/genetics ; Insulin/metabolism ; Insulin-Like Growth Factor I/metabolism ; Insulins/metabolism ; Iridoviridae/genetics ; Iridovirus/genetics ; Mice ; Mice, Inbred C57BL ; Phosphorylation ; Receptor, IGF Type 1/genetics ; Receptor, IGF Type 1/metabolism ; Receptor, Insulin/metabolism ; Signal Transduction
    Chemical Substances Antigens, CD ; IGF1 protein, human ; IGF1R protein, human ; Igf1r protein, mouse ; Insulin ; Insulins ; Insulin-Like Growth Factor I (67763-96-6) ; INSR protein, human (EC 2.7.10.1) ; Receptor, IGF Type 1 (EC 2.7.10.1) ; Receptor, Insulin (EC 2.7.10.1) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2020-11-19
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2708735-9
    ISSN 2212-8778 ; 2212-8778
    ISSN (online) 2212-8778
    ISSN 2212-8778
    DOI 10.1016/j.molmet.2020.101121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: An NAD+ Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death

    Freire, Diana Mendes / Gutierrez, Claude / Garza-Garcia, Acely / Grabowska, Anna D / Sala, Ambre J / Ariyachaokun, Kanchiyaphat / Panikova, Terezie / Beckham, Katherine S.H / Colom, André / Pogenberg, Vivian / Cianci, Michele / Tuukkanen, Anne / Boudehen, Yves-Marie / Peixoto, Antonio / Botella, Laure / Svergun, Dmitri I / Schnappinger, Dirk / Schneider, Thomas R / Genevaux, Pierre /
    de Carvalho, Luiz Pedro Sorio / Wilmanns, Matthias / Parret, Annabel H.A / Neyrolles, Olivier

    Molecular cell. 2019 Jan. 18,

    2019  

    Abstract: Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is ... ...

    Abstract Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is bactericidal unless neutralized by its antitoxin MbcA. To investigate the mechanism, we solved the 1.8 Å-resolution crystal structure of the MbcTA complex. We found that MbcT resembles secreted NAD+-dependent bacterial exotoxins, such as diphtheria toxin. Indeed, MbcT catalyzes NAD+ degradation in vitro and in vivo. Unexpectedly, the reaction is stimulated by inorganic phosphate, and our data reveal that MbcT is a NAD+ phosphorylase. In the absence of MbcA, MbcT triggers rapid M. tuberculosis cell death, which reduces mycobacterial survival in macrophages and prolongs the survival of infected mice. Our study expands the molecular activities employed by bacterial TA modules and uncovers a new class of enzymes that could be exploited to treat tuberculosis and other infectious diseases.
    Keywords Mycobacterium tuberculosis ; animal pathogens ; antitoxins ; bacteria ; catalytic activity ; cell death ; crystal structure ; exotoxins ; macrophages ; mice ; phosphates ; phosphorylase ; therapeutics ; tuberculosis
    Language English
    Dates of publication 2019-0118
    Publishing place Elsevier Inc.
    Document type Article
    Note Pre-press version
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2019.01.028
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Bonn / Germany

    Z 2005/501: Show issues

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  5. Article ; Online: An NAD

    Freire, Diana Mendes / Gutierrez, Claude / Garza-Garcia, Acely / Grabowska, Anna D / Sala, Ambre J / Ariyachaokun, Kanchiyaphat / Panikova, Terezie / Beckham, Katherine S H / Colom, André / Pogenberg, Vivian / Cianci, Michele / Tuukkanen, Anne / Boudehen, Yves-Marie / Peixoto, Antonio / Botella, Laure / Svergun, Dmitri I / Schnappinger, Dirk / Schneider, Thomas R / Genevaux, Pierre /
    de Carvalho, Luiz Pedro Sorio / Wilmanns, Matthias / Parret, Annabel H A / Neyrolles, Olivier

    Molecular cell

    2019  Volume 73, Issue 6, Page(s) 1282–1291.e8

    Abstract: Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is ... ...

    Abstract Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is bactericidal unless neutralized by its antitoxin MbcA. To investigate the mechanism, we solved the 1.8 Å-resolution crystal structure of the MbcTA complex. We found that MbcT resembles secreted NAD
    MeSH term(s) Animals ; Antibiotics, Antitubercular/pharmacology ; Antitoxins/chemistry ; Antitoxins/genetics ; Antitoxins/metabolism ; Bacterial Load ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Bacterial Toxins/chemistry ; Bacterial Toxins/genetics ; Bacterial Toxins/metabolism ; Cells, Cultured ; Disease Models, Animal ; Female ; Host-Pathogen Interactions ; Humans ; Kinetics ; Macrophages/drug effects ; Macrophages/microbiology ; Mice, Inbred C57BL ; Mice, SCID ; Mice, Transgenic ; Microbial Viability ; Models, Molecular ; Mycobacterium smegmatis/enzymology ; Mycobacterium smegmatis/genetics ; Mycobacterium smegmatis/pathogenicity ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/enzymology ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/pathogenicity ; NAD/metabolism ; Phosphorylases/chemistry ; Phosphorylases/genetics ; Phosphorylases/metabolism ; Protein Conformation ; Toxin-Antitoxin Systems/genetics ; Tuberculosis/drug therapy ; Tuberculosis/microbiology
    Chemical Substances Antibiotics, Antitubercular ; Antitoxins ; Bacterial Proteins ; Bacterial Toxins ; NAD (0U46U6E8UK) ; Phosphorylases (EC 2.4.1.-)
    Language English
    Publishing date 2019-02-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2019.01.028
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5055: Show issues Location:
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