A molecular model for the differential activation of STAT3 and STAT6 by the herpesviral oncoprotein tip
Eman Dey Mazumder1, Christophe Jardin, Benjamin Vogel
1Institute for Clinical and Molecular Virology, Universitätsklinikum, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
Abstract:
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.
Insights
Constitutive STAT signaling promotes cancer growth. This study reveals how herpesvirus Tip protein differentially activates STAT3 and STAT6, with STAT6 crucial for virus-induced T cell proliferation, validated by molecular modeling and experiments.
Area of Science:
- Molecular biology
- Virology
- Immunology
Background:
- Constitutive Signal Transducer and Activator of Transcription (STAT) signaling drives malignancy.
- Herpesviral oncoprotein Tip activates STATs via Src kinase, promoting T cell proliferation.
Purpose of the Study:
- To model the interaction between STAT3/STAT6 SH2 domains and herpesviral Tip oncoprotein.
- To elucidate the differential activation of STAT3 and STAT6 by Tip.
- To validate the role of STAT6 in herpesvirus-induced T cell proliferation.
Main Methods:
- Molecular modeling and molecular dynamics simulations.
- Analysis of STAT SH2 domain ligand binding specificity.
- In vitro activation studies with recombinant oncoproteins and viruses.
Main Results:
- A model for STAT SH2 domain interaction with Tip peptides was developed.
- Differential activation of STAT3 and STAT6 by distinct Tip regions was observed.
- STAT6 was experimentally confirmed to be involved in herpesvirus-induced T cell proliferation.
Conclusions:
- The study provides mechanistic insight into STAT activation by viral oncoproteins.
- STAT6 plays a key role in herpesvirus-mediated T cell proliferation.
- Molecular dynamics studies successfully predicted and were validated by experimental findings.
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