Elif Kurt

Suche


A6 Functional selectivity as a result of viral chemokine receptor heterodimerization

Principal investigator
Nuska Tschammer

Mentor
Thomas Stamminger

Functional selectivity as a result of viral chemokine receptor heteromerization

G protein-coupled receptors (GPCRs) represent the largest family of cell surface molecules involved in signal transduction. Certain viruses like human cytomegalovirus (HCMV), Epstein-Barr virus (EBV) and Kaposi's sarcoma herpes virus (KSHV) encode viral G-protein coupled receptors (vGPCRs). The vGPCRs of HCMV are named US27, US28, UL33 and UL78 and have been proposed to promote HCMV replication and dissemination. Several studies suggest that numerous GPCRs are found and function as dimers and/or higher order oligomers at the cell surface. Formation of receptor homodimers and heterodimers in GPCRs has been involved in intracellular trafficking, ligand binding, pharmacologic inhibition, signal transduction, and internalization. Also heterodimer receptor formations often result in a distorted signaling outcome compared to the signaling of homodimers. This phenomenon is known as functional selectivity or biased signaling. It is known that vGPCR can form heterodimers with other vGPCRs and also host's chemokine receptors, but the molecular mechanisms governing heteromerization processes and its functional consequences remain scarcely characterized. Therefore targeting GPCR heteromers constitutes a novel strategy to select receptor-specific responses and is likely to be useful in achieving specific beneficial therapeutic effects. The main goals of this project are the identification of molecular mechanisms governing heteromerization processes and the characterization of changes in the functional response as a consequence of receptor heteromerization. The characterization of changes in the functional response of G proteins upon heteromerization will be undertaken in e.g. complemented donor-acceptor resonance energy transfer assays, which will allow us to achieve the control over the identity of components comprising the signalling unit.

Figure: Expression and signaling of vGPCRs. HCMV infection of human cells leads to the expression of the four viral GPCR US27, US28, UL33, UL78. While the function(s) of US27, UL33 and UL78 in the viral life cycle have not yet been identified, it is known that interactions of US28 with human cell signaling cascades often lead to re-programming of cell signaling that result in a subsequent increase in cell migration, survival, proliferation and viral dissemination.

 

Publications

 

Presentations

July 2013 5th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Functional selectivity as a result of viral chemokine receptor heteromerization
Talk