Biomedical Engineering Reference
In-Depth Information
PhLP1 plays a different role. It stabilizes the interaction between Gb
5
and CCT,
perhaps to increase folding efficiency. After Gb
5
folding PhLP1 must subsequently
release, allowing the RGS protein to bind and form the Gb
5
-RGS dimer directly on
CCT. Gb
5
-RGS is then freed from CCT to interact with its membrane anchoring
protein and form a stable complex that turns off the G protein signal by catalyzing
GTP hydrolysis on Ga .
Keywords
Assembly Chaperone Cytosolic chaperonin containing TCP-1 (CCT)
G protein Phosducin-like protein 1(PhLP1) Protein folding
8.1
G Protein Signaling
Cells detect and respond to a myriad of extracellular signals via seven-transmem-
brane G protein-coupled receptors (GPCR) and their associated G protein signaling
pathways (Wettschureck and Offermanns
2005
). The list of molecules that transmit
signals through GPCRs is impressive, including hormones, neurotransmitters,
chemokines and sensory molecules such as odorants and tastants. Even photons of
light are detected by GPCRs and converted into a neural response by a G protein
pathway in the photoreceptor cells of the retina (Arshavsky et al.
2002
) . Such diverse
signaling requires a large array of receptors, as seen by the nearly 900 genes encoding
different GPCRs in humans (Foord et al.
2005
). The importance of G protein signaling
to human physiology is evidenced by the fact that GPCRs are the target of one third
of currently marketed drugs (DeWire and Violin
2011
) .
The basic architecture of G protein signaling pathways is shown in Fig.
8.1
(Preininger and Hamm
2004
). The pathway is initiated by the binding of the signaling
molecule on the extracellular surface of the GPCR. This interaction causes a confor-
mational change in the receptor which opens up its seven helical bundle on the intra-
cellular surface, exposing the binding site for the G protein (Rasmussen et al.
2011a
;
Standfuss et al.
2011
). In its inactive form, the G protein is a heterotrimer of a , b and
g subunits with GDP bound to the nucleotide binding site on the Ga subunit
(Lambright et al.
1996
; Wall et al.
1995
). Binding to the activated receptor releases
GDP from Ga, allowing GTP to replace GDP in the nucleotide binding site
(Rasmussen et al.
2011b
). The extra phosphate of GTP induces a conformational
change that disrupts the interaction of Ga with the Gb g subunits, causing the disso-
ciation of Ga-GTP from Gb g (Coleman et al.
1994
; Lambright et al.
1994
) . G a -GTP
is then free to interact with effector enzymes such as adenylyl cyclase, phospholipase
Cb or Rho guanine nucleotide exchange factors and regulate their activity (Cabrera-
Vera et al.
2003
) . The G b g pair is an obligate dimer that remains together throughout
its lifetime in the cell (Clapham and Neer
1997
) . Like G a , G b g binds effector
enzymes (Katz et al.
1992
; Pitcher et al.
1992
; Stephens et al.
1994
; Tang and Gilman
1991
) but can also interact with ion channels such as inwardly-rectifying K
+
channels
(Logothetis et al.
1987
; Reuveny et al.
1994
) and voltage-gated Ca
2+
channels
(Herlitze et al.
1996
; Ikeda
1996
). The changes in activity of effector enzymes and
ion channels lead to changes in the cellular concentration of second messengers such
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