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A Process Model of Rho GTP-binding Proteins

A Process Model of Rho GTP-binding Proteins. Luca Cardelli 1, 4 Emmanuelle Caron 2, 4 Philippa Gardner 3, 4 Ozan Kahramanoğulları 3, 4 Andrew Phillips 1 1. Microsoft Research Cambridge 2. Centre for Molecular Biology and Infection, Imperial College

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A Process Model of Rho GTP-binding Proteins

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  1. A Process Model of Rho GTP-binding Proteins Luca Cardelli 1, 4 Emmanuelle Caron2, 4 Philippa Gardner 3, 4Ozan Kahramanoğulları3, 4 Andrew Phillips 1 1. Microsoft Research Cambridge 2. Centre for Molecular Biology and Infection, Imperial College 3. Department of Computing, Imperial College 4. CISBIC, Imperial College 20.11.2007 – CISB’07, Newcastle

  2. Overview • Why Rho GTP-binding proteins? • Why ‘a process model’? • What are we doing? • How are we doing? • Outlook

  3. Modelling FcR-mediated phagocytosis… Opsinized particle binds Fc Receptor. Src is activated. Src phosphorylates two tyrosine residues on ITAM, which then recruits Syk-kinase. Active Syk recruits Vav and activates it. Vav activates Rac. Cdc42 gets activated (somehow).

  4. Cdc42 and Rac are Rho GTP-binding proteins Etienne-Manneville & Hall. Nature 2002 Rho GTP-binding proteins serve as switches that interact with their environment. GEF and GAP are their regulators.

  5. Overview • Why Rho GTP-binding proteins? • Why ‘a process model’? • What are we doing? • How are we doing? • Outlook

  6. Why ‘a process model’? • Process algebra: used to study complex reactive systems • Rich arsenal of mathematical techniques and tools available • Biological systems process information: concurrent, reactive • Complexation can be easily modeled, e.g., actin polymerization. • Process algebra allow modular building of mechanistic models. • Compositionality:

  7. Overview • Why Rho GTP-binding proteins? • Why ‘a process model’? • What are we doing? • How are we doing? • Outlook

  8. An ODE model of Rho GTP-binding Proteins

  9. Overview • Why Rho GTP-binding proteins? • Why ‘a process model’? • What are we doing? • How are we doing? • Outlook

  10. Biological Processes as Computations

  11. Rho GTP-binding Proteins with GEF and without GAP Rho GTP-binding Proteins with GEF and without GAP

  12. Rho GTP-Binding Proteins with GEF and GAP

  13. Extending the Model with GDIs

  14. Parameter analysis for the extended model We vary the parameters of the processes for 4 GDI reactions between 10-4,…,104. r1 =1, r2 =1 r1 =104, r2 =104 r1 =104, r2 =1 r1 =104, r2=10-4 r1=1, r2=10-4 and with varying r3 and r4, there is no effect on the inhibitory behavior of the GDIs. r1=1, r2=104 r1=10-4, r2=104 r1=10-4, r2=10-4

  15. Outlook • A process model of Rho GTP-binding proteins. • Our model successfully mimics the ODE model. • We compositionally extend the model with GDIs. • Parameter estimation by hand (and automated?). • Rho GTP-binding proteins: experimental validation of GDI and active Rho binding. • By composing this model with other components of FcR-mediated phagocytosis, e.g., actin polymerisation, obtain a systems understanding. • Reuse the Rho-GTP model as a template for Ras super-family proteins.

  16. Acknowledgements • Jaroslav Stark • George Tzircotis • Jeroen van Zon • Simon Moon

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