A Process Model of Rho GTPbinding Proteins

1
A Process Model of Rho GTP-binding Proteins

• Luca Cardelli 1, 4 Emmanuelle Caron 2,
  4
• Philippa Gardner 3, 4 Ozan Kahramanogullari
  3, 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 CISB07, 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 r11,
r2 10-4
and with varying r3 and r4, there is no effect on
the inhibitory behavior of the GDIs.

r11, r2104
r110-4, r2104
r110-4, r210-4
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