SUPPLEMENTS (Full Edition)
10 G proteins
|
- A serpentine receptor has 7 transmembrane segments.
Typically it activates a trimeric G protein.
-
A second messenger is a small
molecule that is generated when a signal transduction pathway is
activated. The classic second messenger is cyclic AMP, which is
generated when adenylate cyclase is activated by a G protein (when the
G protein itself was activated by a transmembrane receptor).
|
|
..
|
|
There are two types of G proteins. The
name reflects the ability to bind a guanine nucleotide. The guanine
nucleotide can alternate between GDP and GTP, and controls the activity
of the protein. Both types of G protein work on the same principle that
the GDP-bound form is inactive, and the GTP-bound form is active.
|
|
..
|
|
Trimeric G proteins are associated with the cytosolic face of
the membrane. They are involved in the initial stages of signal
transduction. They are activated by transmembrane receptors, most
typically by serpentine receptors (7-membrane pass proteins).
The three subunits are called α,
β, and γ. The α
subunit binds the guanine nucleotide.
|
|
..
|
|
The inactive form of the G protein is
bound to GDP. In this form, the G protein is constitutively associated
with a membrane receptor. When the receptor is activated (usually by
binding ligand) it causes GDP to be displaced from the G protein.
Because the concentration of GTP in the cytosol is much greater than
that of GDP, the vacant nucleotide binding site is filled with GTP.
|
|
..
|
Figure S32
When a receptor is activated by hormone binding, it causes GTP to replace GDP on a G
subunit. The G
subunit dissociates from the βγ dimer, and activates an effector such as adenylate cyclase.
|
|
..
|
|
Figure S32 shows how trimeric G proteins are activated.
Binding of GTP causes the G protein to dissociate into a free
α subunit and free
βγ dimer.
Depending on the individual G protein, it can be either
the α subunit or
the βγ
dimer that transmits the signal to the next stage in the pathway.
Whichever is the active component (and sometimes both are active) may
either activate or repress the activity of a target protein.
|
|
..
|
|
The target protein often is also associated with the membrane.
This chain of events often stimulates the production of second messenger s.
In one classic example, when the protein Gs is activated, the α
subunit then activates adenylate cyclase, which generates cyclic AMP.
|
|
..
|
|
How long the G protein remains active is controlled by the
α subunit.
All α subunits are GTPases.
When the GTP is hydrolyzed to GDP, the α
subunit reassociates with the βγ
dimer to reconstitute the trimeric G protein. By removing the
individual subunits, the hydrolysis of GTP terminates the physiological
response.
|
|
..
|
|
Each α subunit hydrolyzes its GTP in vitro
at a characteristic (slow) rate, typically with a half-life ~15 secs.
But some of the physiological reactions are much shorter lived. For
example, in the classic system of vision, a light response terminates
in ~100 msec. The rate of GTP hydrolysis can be accelerated in vivo
by interaction with another component of the system. This type of
interaction was originally discovered for monomeric G proteins (see
below), where the relevant component is a called a GAP. A common type
of protein with GAP function for the α
subunits of trimeric G proteins is the RGS (G protein signaling) class
(for review see 2276). An RGS acts indirectly by affecting teh
conformation of the α subunit so that it becomes a more effective GTPase.
|
|
..
|
|
Monomeric G proteins are cytosolic and
are often used as binary switches in signalling or other pathways. They
work on the same principle as the α
subunit of a trimeric G protein. A monomeric G protein is a GTPase that
hydrolyzes its bound GTP. This converts it from an active state to an
inactive state.
|
|
..
|
Figure S33
Monomeric G proteins are active when bound to GTP and inactive when bound to GDP.
Their activity is controlled by other proteins.
|
|
..
|
|
Figure S33 shows that three types of ancillary proteins influence the balance
between the GDP- and GTP-bound forms of a monomeric G protein.
|
|
..
|
-
A
GAP (GTPase activating protein) stimulates the GTPase activity. This is
needed for a fast reaction time, because the intrinsic rate of GTP
hydrolysis is slow. Thus GAP activity inactivates the G protein.
Different GAPs have specificities for different GTP-binding proteins;
they are typically named as Protein-GAP, where Protein is the monomeric G-protein on which they act.
-
A
GEF (guanine nucleotide exchange factor) displaces the GDP bound to an
inactive G protein. The principle of replacement is the same as for the
trimeric α subunit. Release of the GDP
creates an empty site. The concentration of GTP in the cytosol is
greater than that of GDP, so the site is then filled with GTP. This
activates the protein. GEFs have the same sort of specificity as GAPs,
and similarly are named in the form Protein-GEF (for review see 3217).
-
A
GDI (guanine nucleotide dissociation inhibitor) can block the
displacement reaction. This maintains the G protein in the inactive
state.
|
|
..
|
|
Examples of specific monomeric G proteins are EF-Tu (see Elongation factor
Tu loads aminoacyl-tRNA into the A site), Ran (see Transport receptors
carry cargo proteins through the pore), ARF and Rab (see Vesicles can bud
and fuse with membranes), and Ras and the Rho family (see The activation of Ras is controlled by GTP).
|
|
..
|
|
Last Revised on 1-22-2002
|
|
..
|
-
2276 Ross, E. M. and Wilkie, T. M. (2000).
GTPase-activating proteins for heterotrimeric G proteins:
regulators of G protein signaling (RGS) and RGS-like proteins.
Annu. Rev. Biochem. 69, 795-827. PubMed Journal
-
3217 Schmidt, A. and Hall, A.
(2002).
Guanine nucleotide exchange factors for Rho GTPases: turning on the switch.
Genes Dev. 16, 1587-1609.
PubMed Journal
|
|
..
|
|
©Jones and Bartlett Publishers (2007)
|