Transcript Biological Description G Protein Signal Cascade

Description of the G Protein Signal Cascade
Biological Description
G Protein Signal Cascade
Copyright © 1999-2008 by Joyce J. Diwan.
All rights reserved.
Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions
Description of the G Protein Signal Cascade
hormone
signal
outside
GPCR
plasma
membrane
a g
GDP b
GTP
GDP
g  a
AC
b
GTP
cytosol
ATP cAMP + PPi
Turn on of the signal:
1. Initially Ga has bound GDP, and a, b, and g subunits are
complexed together.
Gb,g, the complex of b & g subunits, inhibits Ga.
Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions
Description of the G Protein Signal Cascade
hormone
signal
outside
GPCR
plasma
membrane
a g
GDP b
GTP
GDP
g  a
AC
b
GTP
cytosol
ATP cAMP + PPi
2. Hormone binding, usually to an extracellular domain of a 7-helix
receptor (GPCR), causes a conformational change in the receptor that
is transmitted to a G-protein on the cytosolic side of the membrane.
The nucleotide-binding site on Ga becomes more accessible to the
cytosol, where [GTP] > [GDP].
Ga releases GDP and binds GTP (GDP-GTP exchange).
Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions
Description of the G Protein Signal Cascade
hormone
signal
outside
GPCR
plasma
membrane
a g
GDP b
GTP
GDP
g  a
AC
b
GTP
cytosol
ATP cAMP + PPi
3. Substitution of GTP for GDP causes another conformational
change in Ga.
Ga-GTP dissociates from the inhibitory bg complex and can now
bind to and activate Adenylate Cyclase.
Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions
Description of the G Protein Signal Cascade
hormone
signal
outside
GPCR
plasma
membrane
a g
GDP b
GTP
GDP
g  a
AC
b
GTP
cytosol
ATP cAMP + PPi
4. Adenylate Cyclase, activated by the stimulatory Ga-GTP,
catalyzes synthesis of cAMP.
5. Protein Kinase A (cAMP Dependent Protein Kinase) catalyzes
transfer of phosphate from ATP to serine or threonine residues of
various cellular proteins, altering their activity.
Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions
Description of the G Protein Signal Cascade
Turn off of the signal:
1. Ga hydrolyzes GTP to GDP + Pi. (GTPase).
The presence of GDP on Ga causes it to rebind to the
inhibitory bg complex.
Adenylate Cyclase is no longer activated.
2. Phosphodiesterases catalyze hydrolysis of
cAMP  AMP.
Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions
Description of the G Protein Signal Cascade
Signal amplification is an important feature of signal cascades:
 One hormone molecule can lead to formation of many
cAMP molecules.
 Each catalytic subunit of Protein Kinase A catalyzes
phosphorylation of many proteins during the life-time of
the cAMP.
Using a Timed Concurrent Constraint Process Calculus for Modeling Biomolecular Interactions