Transcript Slide 1

The Activation and
Deactivation of Ras
By Random
Kamil, Ruiyan, and Alina
The Model
 Faeder Model
 Positive Feedback loop with SOS rate
dependence on allosteric binding of activated
RAS
 Michaelis Menten SOS catalyzed nucleotide
exchange
 Hlavacek Model
 Single Step reactions for SOS catalyzed
nucleotide exchange
 Existence of Empty RAS
Ras GTP Activation Threshold
• With positive feedback: 2.10 x 10-8 M
•
Without positive feedback: 7.4 x 10-8 M
Effect of positive feedback loop with 12,000 molecules of SOS
No Positive Feedback
Positive Feedback
Number of SOS Molecules:
2.0e-10*NA*V*600
72,000
Signal causes SOS to be recruited to the membrane
Number of SOS Molecules:
2.0e-10*NA*V*60
7,200
SOS is no longer being recruited
SOS number of molecules:
2.0e-10*NA*V*20
2,400
Even more SOS leaves the
membrane area
Comparing Models with different observables
Ras GTP and GDP
bound to any
molecule
Ras GTP and GDP
Alone
Ras GTP and
GDP Alone
with less
effector binding
Ras GTP and GDP Alone
Effector Activation
High SOS
Low SOS
The Ras Mutation
• Ras still binds to gap, but gap is unable to hydrolyze GTP
• Slow intrinsic hydrolysis still occurs
The Ideal Drug
• Binds to mutated Ras and and gap can now do its job
assisting hydrolysis
Activating Thresholds for Mutated Ras
• Mutated Ras with no drug: 1 x10-8 M
• Mutated Ras with drug: 2.50 x 10-8 M
Mutated Ras
Low SOS Concentration
(2.0e-10*NA*V*60) molecules
7,200 molecules
Ras GTP dominates
Mutated Ras with Drug
Low SOS Concentration
(2.0e-10*NA*V*60) molecules
7,200 molecules
System is turned off
Ras GDP Dominates
Acknowledgement
We want to thank Dr. Jim Faeder and Dr. William Hlavacek for providing
us with the model. We also want to show our deepest appreciation to Dr.
Nancy Griffeth and for Ms. Naralys Batista for their support on our
project as well as the entire CMACS workshop