A molecular model for the differential activation of STAT3 and STAT6 by the herpesviral oncoprotein tip
Constitutive STAT signaling provides growth promoting signals in many forms of malignancy. We performed molecular modeling and molecular dynamics studies of the interaction between the regulatory Src homology 2 (SH2) domains of STAT3 and 6 with phosphorylated peptides of the herpesviral oncoprotein...
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| Veröffentlicht in: | PloS one 2012-04, Vol.7 (4), p.e34306 |
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| creator | Mazumder, Eman Dey Jardin, Christophe Vogel, Benjamin Heck, Elke Scholz, Brigitte Lengenfelder, Doris Sticht, Heinrich Ensser, Armin |
| description | Constitutive STAT signaling provides growth promoting signals in many forms of malignancy. We performed molecular modeling and molecular dynamics studies of the interaction between the regulatory Src homology 2 (SH2) domains of STAT3 and 6 with phosphorylated peptides of the herpesviral oncoprotein Tip, which facilitates Src kinase mediated STAT-activation and T cell proliferation. The studies give insight into the ligand binding specificity of the STAT SH2 domains and provide the first model for the differential activation of STAT3 or STAT6 by two distinct regions of the viral Tip protein. The biological relevance of the modeled interactions was then confirmed by activation studies using corresponding recombinant oncoproteins, and finally by respective recombinant viruses. The functional data give experimental validation of the molecular dynamics study, and provide evidence for the involvement of STAT6 in the herpesvirus induced T cell proliferation. |
| doi_str_mv | 10.1371/journal.pone.0034306 |
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We performed molecular modeling and molecular dynamics studies of the interaction between the regulatory Src homology 2 (SH2) domains of STAT3 and 6 with phosphorylated peptides of the herpesviral oncoprotein Tip, which facilitates Src kinase mediated STAT-activation and T cell proliferation. The studies give insight into the ligand binding specificity of the STAT SH2 domains and provide the first model for the differential activation of STAT3 or STAT6 by two distinct regions of the viral Tip protein. The biological relevance of the modeled interactions was then confirmed by activation studies using corresponding recombinant oncoproteins, and finally by respective recombinant viruses. The functional data give experimental validation of the molecular dynamics study, and provide evidence for the involvement of STAT6 in the herpesvirus induced T cell proliferation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0034306</identifier><identifier>PMID: 22509288</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation analysis ; Amino Acid Sequence ; Amino acids ; Analysis ; B cells ; Binding sites ; Biochemistry ; Bioinformatics ; Biology ; Cell activation ; Cell proliferation ; Cell Transformation, Viral ; Cytokines ; Deoxyribonucleic acid ; DNA ; DNA, Recombinant - genetics ; E coli ; Escherichia coli ; Genomes ; HEK293 Cells ; HeLa Cells ; Herpes viruses ; Herpesviridae - genetics ; Homology ; Humans ; Ligands ; Lymphocytes ; Lymphocytes T ; Lymphoma ; Malignancy ; Medicine ; Molecular dynamics ; Molecular Dynamics Simulation ; Molecular modelling ; Molecular Sequence Data ; Oncogene Proteins - chemistry ; Oncogene Proteins - metabolism ; Oncoproteins ; Peptides ; Phosphorylation ; Proteins ; Signaling ; src Homology Domains ; Src protein ; Stat3 protein ; STAT3 Transcription Factor - chemistry ; STAT3 Transcription Factor - metabolism ; Stat6 protein ; STAT6 Transcription Factor - chemistry ; STAT6 Transcription Factor - metabolism ; Substrate Specificity ; T cells ; T-Lymphocytes - virology ; Trends ; Tyrosine ; Viral Proteins - chemistry ; Viral Proteins - metabolism ; Virology ; Viruses</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e34306</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Mazumder et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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We performed molecular modeling and molecular dynamics studies of the interaction between the regulatory Src homology 2 (SH2) domains of STAT3 and 6 with phosphorylated peptides of the herpesviral oncoprotein Tip, which facilitates Src kinase mediated STAT-activation and T cell proliferation. The studies give insight into the ligand binding specificity of the STAT SH2 domains and provide the first model for the differential activation of STAT3 or STAT6 by two distinct regions of the viral Tip protein. The biological relevance of the modeled interactions was then confirmed by activation studies using corresponding recombinant oncoproteins, and finally by respective recombinant viruses. The functional data give experimental validation of the molecular dynamics study, and provide evidence for the involvement of STAT6 in the herpesvirus induced T cell proliferation.</description><subject>Activation analysis</subject><subject>Amino Acid Sequence</subject><subject>Amino acids</subject><subject>Analysis</subject><subject>B cells</subject><subject>Binding sites</subject><subject>Biochemistry</subject><subject>Bioinformatics</subject><subject>Biology</subject><subject>Cell activation</subject><subject>Cell proliferation</subject><subject>Cell Transformation, Viral</subject><subject>Cytokines</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA, Recombinant - genetics</subject><subject>E coli</subject><subject>Escherichia coli</subject><subject>Genomes</subject><subject>HEK293 Cells</subject><subject>HeLa Cells</subject><subject>Herpes viruses</subject><subject>Herpesviridae - genetics</subject><subject>Homology</subject><subject>Humans</subject><subject>Ligands</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Lymphoma</subject><subject>Malignancy</subject><subject>Medicine</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular modelling</subject><subject>Molecular Sequence Data</subject><subject>Oncogene Proteins - 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genetics</topic><topic>E coli</topic><topic>Escherichia coli</topic><topic>Genomes</topic><topic>HEK293 Cells</topic><topic>HeLa Cells</topic><topic>Herpes viruses</topic><topic>Herpesviridae - genetics</topic><topic>Homology</topic><topic>Humans</topic><topic>Ligands</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Lymphoma</topic><topic>Malignancy</topic><topic>Medicine</topic><topic>Molecular dynamics</topic><topic>Molecular Dynamics Simulation</topic><topic>Molecular modelling</topic><topic>Molecular Sequence Data</topic><topic>Oncogene Proteins - chemistry</topic><topic>Oncogene Proteins - metabolism</topic><topic>Oncoproteins</topic><topic>Peptides</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Signaling</topic><topic>src Homology Domains</topic><topic>Src protein</topic><topic>Stat3 protein</topic><topic>STAT3 Transcription Factor - chemistry</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Stat6 protein</topic><topic>STAT6 Transcription Factor - 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We performed molecular modeling and molecular dynamics studies of the interaction between the regulatory Src homology 2 (SH2) domains of STAT3 and 6 with phosphorylated peptides of the herpesviral oncoprotein Tip, which facilitates Src kinase mediated STAT-activation and T cell proliferation. The studies give insight into the ligand binding specificity of the STAT SH2 domains and provide the first model for the differential activation of STAT3 or STAT6 by two distinct regions of the viral Tip protein. The biological relevance of the modeled interactions was then confirmed by activation studies using corresponding recombinant oncoproteins, and finally by respective recombinant viruses. 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| subjects | Activation analysis Amino Acid Sequence Amino acids Analysis B cells Binding sites Biochemistry Bioinformatics Biology Cell activation Cell proliferation Cell Transformation, Viral Cytokines Deoxyribonucleic acid DNA DNA, Recombinant - genetics E coli Escherichia coli Genomes HEK293 Cells HeLa Cells Herpes viruses Herpesviridae - genetics Homology Humans Ligands Lymphocytes Lymphocytes T Lymphoma Malignancy Medicine Molecular dynamics Molecular Dynamics Simulation Molecular modelling Molecular Sequence Data Oncogene Proteins - chemistry Oncogene Proteins - metabolism Oncoproteins Peptides Phosphorylation Proteins Signaling src Homology Domains Src protein Stat3 protein STAT3 Transcription Factor - chemistry STAT3 Transcription Factor - metabolism Stat6 protein STAT6 Transcription Factor - chemistry STAT6 Transcription Factor - metabolism Substrate Specificity T cells T-Lymphocytes - virology Trends Tyrosine Viral Proteins - chemistry Viral Proteins - metabolism Virology Viruses |
| title | A molecular model for the differential activation of STAT3 and STAT6 by the herpesviral oncoprotein tip |
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