Try the new BioModels platform (beta)
BioModels Database logo

BioModels Database

spacer

BIOMD0000000692 - Phillips2003 - The Mechanism of Ras GTPase Activation by Neurofibromin

 

 |   |   |  Send feedback
Reference Publication
Publication ID: 12667087
Phillips RA, Hunter JL, Eccleston JF, Webb MR.
The mechanism of Ras GTPase activation by neurofibromin.
Biochemistry 2003 Apr; 42(13): 3956-3965
National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom.  [more]
Model
Original Model: DOQCS logo
Submitter: Sharat Vayttaden
Submission ID: MODEL4968912141
Submission Date: 26 Jan 2007 18:50:58 UTC
Last Modification Date: 19 Mar 2018 16:14:11 UTC
Creation Date: 19 Mar 2018 15:37:09 UTC
Encoders:  Matthew Grant Roberts
set #1
bqbiol:hasPart KEGG Orthology K08052
bqbiol:isPartOf KEGG Pathway ko04014
bqbiol:isVersionOf Gene Ontology regulation of Ras GTPase binding
bqbiol:hasTaxon Taxonomy Escherichia coli
bqbiol:isDescribedBy PubMed 12667087
set #2
bqmodel:is BioModels Database Phillips2003_RasGTPase
Notes
Phillips2003 - The Mechanism of Ras GTPase Activation by Neurofibromin
A mathematical model for Ras-GTP activation by neurofibromin and the kinetic rates of the relevant reactions.

This model is described in the article:

Phillips RA, Hunter JL, Eccleston JF, Webb MR.
Biochemistry 2003 Apr; 42(13): 3956-3965

Abstract:

Individual rate constants have been determined for each step of the Ras.GTP hydrolysis mechanism, activated by neurofibromin. Fluorescence intensity and anisotropy stopped-flow measurements used the fluorescent GTP analogue, mantGTP (2'(3')-O-(N-methylanthraniloyl)GTP), to determine rate constants for binding and release of neurofibromin. Quenched flow measurements provided the kinetics of the hydrolytic cleavage step. The fluorescent phosphate sensor, MDCC-PBP was used to measure phosphate release kinetics. Phosphate-water oxygen exchange, using (18)O-substituted GTP and inorganic phosphate (P(i)), was used to determine the extent of reversal of the hydrolysis step and of P(i) binding. The data show that neurofibromin and P(i) dissociate from the NF1.Ras.GDP.P(i) complex with identical kinetics, which are 3-fold slower than the preceding cleavage step. A model is presented in which the P(i) release is associated with the change of Ras from "GTP" to "GDP" conformation. In this model, the conformation change on P(i) release causes the large change in affinity of neurofibromin, which then dissociates rapidly.

This model is hosted on BioModels Database and identified by: BIOMD0000000692.

To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 12667087 Submission Date: 26 Jan 2007 18:50:58 UTC Last Modification Date: 19 Mar 2018 16:14:11 UTC Creation Date: 19 Mar 2018 15:37:09 UTC
Mathematical expressions
Reactions
GTP_hydrolysis_sbo_1_sbc_ GTP_hydrolysis_sbo_2_sbc_ Ras_activation GAP_dissociation
NF1_binding      
Rules
Assignment Rule (variable: Pi_curve) Assignment Rule (variable: hplc_curve)    
Physical entities
Compartments Species
E. coli Pi RasGTP RasGTP_minus_NF1
RasGTP_minus_NF1_star_ RasGDP_minus_NF1_Pi RasGDP_NF1
RasGDP NF1  
Global parameters
Pi_curve hplc_curve    
Reactions (5)
 
 GTP_hydrolysis_sbo_1_sbc_ [RasGTP_minus_NF1_star_] ↔ [RasGDP_minus_NF1_Pi];  
 
 GTP_hydrolysis_sbo_2_sbc_ [RasGDP_minus_NF1_Pi] ↔ [Pi] + [RasGDP_NF1];  
 
 Ras_activation [RasGTP_minus_NF1] ↔ [RasGTP_minus_NF1_star_];  
 
 GAP_dissociation [RasGDP_NF1] ↔ [RasGDP] + [NF1];  
 
 NF1_binding [RasGTP] + [NF1] ↔ [RasGTP_minus_NF1];  
 
Rules (2)
 
 Assignment Rule (name: Pi_curve) Pi_curve = 100*(Pi-1)/1
 
 Assignment Rule (name: hplc_curve) hplc_curve = RasGTP*100/1
 
Functions (5)
 
 Function for GTP_hydrolysis_sbo_2_sbc_ lambda(Pi, RasGDP_NF1, RasGDP_minus_NF1_Pi, geometry, kb, kf, (kf*RasGDP_minus_NF1_Pi-kb*Pi*RasGDP_NF1)/geometry)
 
 Function for NF1_binding lambda(NF1, RasGTP, RasGTP_minus_NF1, geometry, kb, kf, (kf*RasGTP*NF1-kb*RasGTP_minus_NF1)/geometry)
 
 Function for Ras_activation lambda(RasGTP_minus_NF1, RasGTP_minus_NF1_star_, geometry, kb, kf, (kf*RasGTP_minus_NF1-kb*RasGTP_minus_NF1_star_)/geometry)
 
 Function for GAP_dissociation lambda(NF1, RasGDP, RasGDP_NF1, geometry, kb, kf, (kf*RasGDP_NF1-kb*RasGDP*NF1)/geometry)
 
 Function for GTP_hydrolysis_sbo_1_sbc_ lambda(RasGDP_minus_NF1_Pi, RasGTP_minus_NF1_star_, geometry, kb, kf, (kf*RasGTP_minus_NF1_star_-kb*RasGDP_minus_NF1_Pi)/geometry)
 
 E. coli Spatial dimensions: 3.0  Compartment size: 5.236E-13
 
 Pi
Compartment: E. coli
Initial concentration: 1.0
 
 RasGTP
Compartment: E. coli
Initial concentration: 1.0
 
 RasGTP_minus_NF1
Compartment: E. coli
Initial concentration: 0.0
 
 RasGTP_minus_NF1_star_
Compartment: E. coli
Initial concentration: 0.0
 
 RasGDP_minus_NF1_Pi
Compartment: E. coli
Initial concentration: 0.0
 
 RasGDP_NF1
Compartment: E. coli
Initial concentration: 0.0
 
 RasGDP
Compartment: E. coli
Initial concentration: 0.0
 
 NF1
Compartment: E. coli
Initial concentration: 9.99936338171632
 
Global Parameters (2)
 
  Pi_curve  
 
  hplc_curve
Value: 100.0
 
GTP_hydrolysis_sbo_1_sbc_ (2)
 
   kb
Value: 1.15192E-13
Constant
 
   kf
Value: 1.02102E-11
Constant
 
GTP_hydrolysis_sbo_2_sbc_ (2)
 
   kb
Value: 5.65482E-17
Constant
 
   kf
Value: 2.0944E-11
Constant
 
Ras_activation (2)
 
   kb
Value: 2.8798E-12
Constant
 
   kf
Value: 2.18865E-10
Constant
 
GAP_dissociation (2)
 
   kb
Value: 6.28318E-13
Constant
 
   kf
Value: 2.43474E-11
Constant
 
NF1_binding (2)
 
   kb
Value: 3.3301E-12
Constant
 
   kf
Value: 6.28318E-13
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000692

Curator's comment: (updated: 22 Mar 2018 10:51:48 GMT)

The model as such reproduces figure 4 of the reference publication. The figure shows the percentage change in P_i (inorganic phosphate) and the percentage of hlpc (RasGTP) remaining. The simulation was performed in COPASI 4.22 (Build 170) and the figure was generated in MATLAB R2014b.

Additional file(s)
spacer
spacer