33
3
than GDP, G-proteins, in a nonactivated state, are bound to GDP. This tight binding has
to be actively released by GEFs (guanyl nucleotide exchange factors). In the case of GPCR
signalling, the ligand-bound receptor usually acts as GEF, leading to GDP release and GTP
binding. In this conformation the switch is on (see . Fig. 3.2).
The GTP-bound α-subunit of trimeric G-proteins dissociates from the β/γ-subunits and
moves away from the complex to interact with target enzymes. Major target enzymes of
activated α-subunits of trimeric G-proteins are adenylyl cyclase, phosphodiesterase and
phospholipase C (see . Figs. 3.1b and 3.3). In addition, several ion channels are regulated
in response to GPCR-activated trimeric G-proteins. Lastly, α-subunits of trimeric
G- proteins can activate mitogen-activated kinases (MAP kinases) (Sugden and Clerk 1997).
On
Off
RGS (Regulator of G-protein Signalling)
= GAP (GTPase Activating Protein)
Ligand-bound GPCR
= GEF (Guanyl nucleotide Exchange Factor)
GDP
α
β γ
GTP
α
β γ
P
. Fig. 3.2 Schematic representation of membrane-anchored trimeric G-proteins and G-protein cycle
of α-subunits. “On” state with GTP-bound and dissociated α-subunit, ligand-bound receptor functions
as GEF; “off” state with GDP-bound, α-subunit functions as GTPase; GTPase activity is regulated by RGS
proteins working as GAPs. Gα-GDP reassembles with Gβ/γ
Box 3.2 Small G-proteins or small GTPases
Small G-proteins are monomeric GTP-binding proteins with low intrinsic GTPase activity (20–
40 kDa). GTPase activity can be stimulated by GTPase-activating proteins (GAPs). GTP loading is
always assisted by guanyl nucleotide exchange factors (GEFs). Small G-proteins act as molecular
switches in many cellular processes including mitogenic signalling (Ras family), cytoskeletal signalling (Rho family), nuclear import/export (Ran family), vesicle transport (Rab and Arf/Sar families) and cell adhesion and migration (Rap family). Large families of GEFs and GAPs exist for each
small G-protein, and these are important regulators of the respective cellular functions.
3.2 · Trimeric G-Proteins
3
than GDP, G-proteins, in a nonactivated state, are bound to GDP. This tight binding has
to be actively released by GEFs (guanyl nucleotide exchange factors). In the case of GPCR
signalling, the ligand-bound receptor usually acts as GEF, leading to GDP release and GTP
binding. In this conformation the switch is on (see . Fig. 3.2).
The GTP-bound α-subunit of trimeric G-proteins dissociates from the β/γ-subunits and
moves away from the complex to interact with target enzymes. Major target enzymes of
activated α-subunits of trimeric G-proteins are adenylyl cyclase, phosphodiesterase and
phospholipase C (see . Figs. 3.1b and 3.3). In addition, several ion channels are regulated
in response to GPCR-activated trimeric G-proteins. Lastly, α-subunits of trimeric
G- proteins can activate mitogen-activated kinases (MAP kinases) (Sugden and Clerk 1997).
On
Off
RGS (Regulator of G-protein Signalling)
= GAP (GTPase Activating Protein)
Ligand-bound GPCR
= GEF (Guanyl nucleotide Exchange Factor)
GDP
α
β γ
GTP
α
β γ
P
. Fig. 3.2 Schematic representation of membrane-anchored trimeric G-proteins and G-protein cycle
of α-subunits. “On” state with GTP-bound and dissociated α-subunit, ligand-bound receptor functions
as GEF; “off” state with GDP-bound, α-subunit functions as GTPase; GTPase activity is regulated by RGS
proteins working as GAPs. Gα-GDP reassembles with Gβ/γ
Box 3.2 Small G-proteins or small GTPases
Small G-proteins are monomeric GTP-binding proteins with low intrinsic GTPase activity (20–
40 kDa). GTPase activity can be stimulated by GTPase-activating proteins (GAPs). GTP loading is
always assisted by guanyl nucleotide exchange factors (GEFs). Small G-proteins act as molecular
switches in many cellular processes including mitogenic signalling (Ras family), cytoskeletal signalling (Rho family), nuclear import/export (Ran family), vesicle transport (Rab and Arf/Sar families) and cell adhesion and migration (Rap family). Large families of GEFs and GAPs exist for each
small G-protein, and these are important regulators of the respective cellular functions.
3.2 · Trimeric G-Proteins