GPCR Cycle Flashcards
The main feature of GPCRs
Seven transmembrane spanning segments, which position the N-terminus of the protein on the outside of the cell and the C-terminus inside
What do GPCR’s bind?
diverse set of ligands – proteins, small molecules, hormones, drugs, photons
How do ligands typically bind to GPCR’s?
capturing the ligand with their N-terminus and/or with a pocket formed by the extracellular and transmembrane domains
Why is the GPCR cycle useful?
elegant cellular solution for sensing a specific exogenous signal, transducing it to a signalling cascade, and then terminating the signal
GPCRs are dynamic proteins that
fluctuate between many states
What happens when ligands bind to GPCR’s (who)?
Ligand binding stabilizes the GPCR into an ‘on’ position, which is further stabilized by binding of a G-protein (Kobika, 2012).
What are the effectors of GPCR activation?
Heterotrimeric G-proteins Gα, Gβ and Gγ
What underlies differential GPCR signalling?
Organisms encode several types of each G-protein, and different combinations of these proteins into heterotrimers preferentially activate different signaling pathways
What are Gα proteins?
Gα proteins are GTPases, which catalyzes the hydrolysis of GTP to GDP
Where can you typically find Gα proteins (who)?
Gα proteins are typically anchored in the membrane by N-terminal palmitoylation and can also be myristoylated (Vögler et al., 2008)
What post translational modifications are seen on Gγ proteins (who)?
isoprenylated at their C-terminal CAAX motif (Higgins and Caseys, 1994)
Why do Gβ proteins associate with Gγ (who)?
Gβ proteins do not have any membrane-anchoring posttranslational modifications. Instead, they are tightly linked to Gγ through hydrophobic interactions (Sondek et al., 1996).
How does interaction of heterotrimeric G protein complexes differ with inactivated GPCR’s and ligand-bound GPCR?
A heterotrimeric complex can dock to an inactivated receptor or drift in the membrane, but once it encounters a ligand-bound GPCR, downstream signaling is initiated
What do activated GPCR’s act as?
Guanine nucleotide exchange factors (GEFs) that exchange GDP for GTP in the Gα subunit, which activates the protein
What happens when GTP binds to Gα?
Upon GTP binding, Gα changes its conformation, allowing it to separate from the Gβγ dimer. The subunits are then free to interact with downstream targets
