Abstract
Thirty years after the first description and modeling of G protein coupled receptors (GPCRs), information about their mode of action is still limited. One of the questions that is hard to answer is: how do the allosteric changes in the GPCR induced by, e.g., ligand binding in the end activate a G protein-dependent intracellular pathway (e.g., via the cAMP or the phosphatidylinositol signal pathways). Another question relates to the role of prenylation of G proteins. Today’s “consensus model” states that protein prenylation is required for the assembly of GPCR-G protein complexes. Although it is well-known that protein prenylation is the covalent addition of a farnesyl- or geranylgeranyl moiety to the C terminus of specific proteins, e.g., α or γ G protein, the reason for this strong covalent binding remains enigmatic. The arguments for a fundamental role for prenylation of G proteins other than just being a hydrophobic linker, are gradually accumulating. We uncovered a dilemma that at first glance may be considered physiologically irrelevant, however, it may cause a true change in paradigm. The consensus model suggests that the only functional role of prenylation is to link the G protein to the receptor. Does the isoprenoid nature of the prenyl group and its exact site of attachment somehow matter? Or, are there valid arguments favoring the alternative possibility that a key role of the G protein is to guide the covalently attached prenyl group to – and it hold it in – a very specific location in between specific helices of the receptor? Our model says that the farnesyl/prenyl group – aided by its covalent attachment to a G protein -might function in GPCRs as a horseshoe-shaped flexible (and perhaps flip-flopping) hydrophobic valve for restricting (though not fully inhibiting) the untimely passage of Ca2+, like retinal does for the passage of H+ in microbial rhodopsins that are ancestral to many GPCRs.
Highlights
There must be a cell-physiological necessity why many ligands use a complex G protein coupled receptors (GPCRs), of which the folded protein chain passes through the cell membrane seven times (7 TM receptors) for signaling
The mechanism we propose is neither in conflict with the “consensus model” nor with recent detailed molecular models for GPCR activation obtained with solid-state NMR (Kimata et al, 2015) and CryoEM (Liang et al, 2017, 2018; Kang et al, 2018; Safdari et al, 2018)
The unanswered key question is that it seems to be theoretically possible, for farnesyl to flip-flop under physiological conditions, e.g., inside a GPCR, does it really happen? And, if it does, is such flip-flopping isomerization somehow linked with the changes in the 3D conformation ( = allosteric change) that take place when a ligand attaches to its matching binding pocket inside a GPCR? To our knowledge, this has never been investigated, probably because the physiological importance of such study was not apparent in the past
Summary
There must be a cell-physiological necessity why many ligands use a complex GPCR, of which the folded protein chain passes through the cell membrane seven times (7 TM receptors) for signaling. Does the attachment of a farnesyl-group to a G-protein represent a functional substitute for the “chemical (flip-flop) valve function” of ancient microbial retinal?
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
