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The Activation and Deactivation of Ras

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

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The Activation and Deactivation of Ras

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  1. The Activation and Deactivation of Ras ByRandom Kamil, Ruiyan, and Alina

  2. The Model • Faeder Model • Positive Feedback loop with SOS rate dependence on allosteric binding of activated RAS • MichaelisMenten SOS catalyzed nucleotide exchange • Hlavacek Model • Single Step reactions for SOS catalyzed nucleotide exchange • Existence of Empty RAS

  3. With positive feedback: 2.10 x 10-8 M Ras GTP Activation Threshold • Without positive feedback: 7.4 x 10-8 M

  4. Effect of positive feedback loop with 12,000 molecules of SOS No Positive Feedback Positive Feedback

  5. Number of SOS Molecules: 2.0e-10*NA*V*600 72,000 Signal causes SOS to be recruited to the membrane

  6. Number of SOS Molecules: 2.0e-10*NA*V*60 7,200 SOS is no longer being recruited

  7. SOS number of molecules: 2.0e-10*NA*V*20 2,400 Even more SOS leaves the membrane area

  8. 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

  9. Effector Activation High SOS Low SOS

  10. 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 mutatedRas and and gap can now do its job assisting hydrolysis

  11. Activating Thresholds for Mutated Ras • Mutated Ras with no drug: 1 x10-8 M • Mutated Ras with drug: 2.50 x 10-8 M

  12. Mutated Ras Low SOS Concentration (2.0e-10*NA*V*60) molecules 7,200 molecules Ras GTP dominates

  13. Mutated Ras with Drug Low SOS Concentration (2.0e-10*NA*V*60) molecules 7,200 molecules System is turned off Ras GDP Dominates

  14. 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

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