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

• With positive feedback: 2.10 x 10-8 M

Ras GTP Activation Threshold

• 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

Ras GTP and GDP Alone

with less effector binding

High SOS

Low SOS

Effector Activation

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) molecules7,200 molecules

Ras GTP dominates

Mutated Ras with Drug Low SOS Concentration

(2.0e-10*NA*V*60) molecules7,200 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