"UNDERSTANDING G-PROTEIN-COUPLED-RECEPTOR (GPCR) SIGNALING FROM ATOMISTIC MOLECULAR DYNAMICS SIMULATIONS" başlıklı seminer Dr. Özge Şensoy tarafından 9 Şubat Pazartesi günü saat 14:00'da İTÜ UHEM toplantı salonunda yapılacaktır.
The Nobel Prize award to Lefkowitz and Kobilka underscores the extraordinary progress achieved in understanding some of the most important molecular machines in cell function and signaling: G-protein-coupled-receptors (GPCRs), which are responsible for transmitting extracellular signals to the inside of the cell by coupling to heterotrimeric G-proteins. Elements of the complex signaling interaction network have become clearer from accumulating structural information at the molecular level. Based on such information, detailed attention was accorded to the function-related conformational changes in the TM bundle of GPCRs, but less so to the amphipathic helical motif, Helix-8 (Hx8), which is located immediately after the end of the seventh transmembrane domain. Yet the conservation of such a structure in nearly all GPCRs and its involvement in various cellular processes such as G-protein coupling, receptor expression, and internalization suggests a specific role for this domain in GPCR signaling.
Furthermore, the discovery of G-protein-independent signaling, notably those mediated by Arrestins (Arrs) has changed the classical view of GPCR signaling where Arrs were previously thought to mediate exclusively desensitization and, in some cases, internalization processes. A key set of questions raised by the availability of multiple signaling pathways then is how the relative efficacy of engaging a certain signaling effector (G-protein or Arr) depends on the ligand that activates the receptor. This ligand-dependent-selectivity for coupling to a specific signaling pathway is known as “functional selectivity”, and is mediated by biased ligands. While rapid progress is being made in this field, we are still far from understanding of molecular mechanisms responsible for specific engagement of GPCRs with a certain signaling effector.
In this talk, I will recapitulate strategies –along with corresponding results- used to address the abovementioned open questions in the field. Correspondingly, in the first part of the talk, I will present recent results concerning the mechanistic role of Hx-8 in interactions of GPCRs with PDZ-domain containing proteins. In the second part, I will discuss the likelihood structural basis for intriguing functional selectivity displayed by the Arr family towards the phosphorylation state of the receptor with more emphasis on its relevance to functional complementation approaches. Finally, I will briefly discuss the concept of “biased signaling” in the context of targeted drug design strategies.
I received my B.S degree from Istanbul Technical University in Molecular Biology and Genetics with a double major in Chemistry. Upon graduation, I continued my M.Sc and PhD studies at Koc University in the department of Computational Sciences and Engineering. In particular, I worked with peptide-based nanomaterials that found applications in various areas such as drug design, tissue engineering, etc. Currently, I work as a post-doctoral associate at Weinstein’s Laboratory at Weill Cornell Medical College. I have been involved in various projects centered on investigation of the mechanism underlying the cell signaling phenomenon.