Chaperone-Mediated Assembly of G Protein Complexes - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 127

Fig. 8.1 The G protein signaling cycle. The scheme depicts the G protein activation/inactivation
cycle using the atomic structures of the individual components determined by X-ray crystallogra-
phy. The entire cycle occurs on the plasma membrane with all components associated with the
inner leaflet of the plasma membrane, or spanning the membrane in the case of the GPCR, and is
only shown displaced from the membrane for clarity purposes. See text for a description of the
cycle. Color code for the proteins is: GPCR - green , G a - teal , G b 1 - blue , G g - red , RGS DEP/
DHEX domain - pink , G b 5 - dark blue , RGS Gg-like domain - dark red , RGS domain - orange .
PDB numbers for the various structures are: GPCR-G protein complex (3SN6) (Rasmussen et al.
2011b ), G protein heterotrimer (1GOT) (Lambright et al. 1996 ) , G a-GTP (1TND) (Noel et al.
1993 ) , G b 5 -RGS (1 PB1) (Cheever et al. 2008 )
These changes then drive the cellular response to the signal. The signal is turned off
by the action of regulators of G protein signaling (RGS) proteins that catalyze the
hydrolysis of GTP to GDP on Ga, allowing the reassociation of Ga-GDP with Gb g
and returning the system to its inactive state (Kimple et al. 2011 ) .
In order for GPCRs, G proteins and effectors to perform these functions, they
must first be synthesized, and their nascent chains must find their binding partners
and move to the plasma membrane where the initial signaling events occur. Of the
many diseases associated with malfunctions in G protein pathways, an important
subset results from misfolding mutations in GPCRs or other pathway components
that disrupt trafficking of the GPCR and assembly of the G protein and effector
complexes (Conn et al. 2007 ; Kosmaoglou et al. 2008 ; Williams and Devi 2011 ;
Grau et al. 2011 ; Tummala et al. 2011 ; Weinstein et al. 2006 ). Thus, it has become
increasingly important to understand the folding pathways of the receptors and
other components of the G protein pathway as evidenced by the extensive research
efforts described in this volume.