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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 - PowerPoint PPT Presentation
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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 Cambridge2. Centre for Molecular Biology and Infection, Imperial College
3. Department of Computing, Imperial College4. CISBIC, Imperial College
20.11.2007 – CISB’07, Newcastle
Overview
• Why Rho GTP-binding proteins?
• Why ‘a process model’?
• What are we doing?
• How are we doing?
• Outlook
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).
Cdc42 and Rac are Rho GTP-binding proteins
Rho GTP-binding proteins serve as switches that interact with their environment.
GEF and GAP are their regulators.
Etienne-Manneville & Hall. Nature 2002
Overview
• Why Rho GTP-binding proteins?
• Why ‘a process model’?
• What are we doing?
• How are we doing?
• Outlook
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:
Overview
• Why Rho GTP-binding proteins?
• Why ‘a process model’?
• What are we doing?
• How are we doing?
• Outlook
An ODE model of Rho GTP-binding Proteins
Overview
• Why Rho GTP-binding proteins?
• Why ‘a process model’?
• What are we doing?
• How are we doing?
• Outlook
Biological Processes as Computations
Rho GTP-binding Proteins with GEF and without GAP
Rho GTP-binding Proteins with GEF and without GAP
Rho GTP-Binding Proteins with GEF and GAP
Extending the Model with GDIs
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
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.
Acknowledgements
• Jaroslav Stark
• George Tzircotis
• Jeroen van Zon
• Simon Moon