Phillips2003 - The Mechanism of Ras GTPase Activation by Neurofibromin
This model is described in the article:
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.
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The mechanism of Ras GTPase activation by neurofibromin.
- Phillips RA, Hunter JL, Eccleston JF, Webb MR
- Biochemistry , 4/ 2003 , Volume 42 , Issue 13 , pages: 3956-3965 , PubMed ID: 12667087
- National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom.
- 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.
Submitter of this revision: administrator
Modellers: administrator, Sharat Vayttaden
Metadata information
isDescribedBy (2 statements)
hasTaxon (1 statement)
isVersionOf (1 statement)
hasPart (1 statement)
isPartOf (1 statement)
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SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| BIOMD0000000692_url.xml | SBML L2V4 representation of Phillips2003 - The Mechanism of Ras GTPase Activation by Neurofibromin | 42.94 KB | Preview | Download |
Additional files |
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| BIOMD0000000692-biopax3.owl | Auto-generated BioPAX (Level 3) | 19.49 KB | Preview | Download |
| BIOMD0000000692.m | Auto-generated Octave file | 6.69 KB | Preview | Download |
| BIOMD0000000692.pdf | Auto-generated PDF file | 165.96 KB | Preview | Download |
| BIOMD0000000692.png | Auto-generated Reaction graph (PNG) | 36.69 KB | Preview | Download |
| BIOMD0000000692.sci | Auto-generated Scilab file | 3.10 KB | Preview | Download |
| BIOMD0000000692.svg | Auto-generated Reaction graph (SVG) | 12.61 KB | Preview | Download |
| BIOMD0000000692.vcml | Auto-generated VCML file | 971.00 Bytes | Preview | Download |
| BIOMD0000000692.xpp | Auto-generated XPP file | 4.64 KB | Preview | Download |
| BIOMD0000000692_urn.xml | Auto-generated SBML file with URNs | 42.90 KB | Preview | Download |
| MODEL4968912141.cps | Curated and annotated model COPASI file. | 57.81 KB | Preview | Download |
| MODEL4968912141.sedml | SED-ML file for figure 4. | 2.27 KB | Preview | Download |
- Model originally submitted by : Sharat Vayttaden
- Submitted: Jan 26, 2007 6:50:58 PM
- Last Modified: Mar 19, 2018 4:14:11 PM
Revisions
-
Version: 3
- Submitted on: Mar 19, 2018 4:14:11 PM
- Submitted by: administrator
- With comment: Notes updated using online editor.
-
Version: 2
- Submitted on: Jul 15, 2007 3:41:00 PM
- Submitted by: Sharat Vayttaden
- With comment: Current version of Phillips2003_RasGTPase
-
Version: 1
- Submitted on: Jan 26, 2007 6:50:58 PM
- Submitted by: Sharat Vayttaden
- With comment: Original import of RasGTPase
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: Variable used inside SBML models
| Species | Initial Concentration/Amount |
|---|---|
| Pi inorganic phosphate |
1.0 μmol |
| NF1 K08052 |
9.99936338171632 μmol |
| RasGDP GDP ; 43873 |
0.0 μmol |
| RasGTP minus NF1 K08052 ; GTP ; 43873 |
0.0 μmol |
| RasGTP minus NF1 star K08052 ; GTP ; 43873 |
0.0 μmol |
| RasGTP GTP ; 43873 |
1.0 μmol |
| RasGDP minus NF1 Pi GDP ; inorganic phosphate ; K08052 ; 43873 |
0.0 μmol |
| Reactions | Rate | Parameters |
|---|---|---|
| RasGDP_minus_NF1_Pi => Pi + RasGDP_NF1 | geometry*(kf*RasGDP_minus_NF1_Pi-kb*Pi*RasGDP_NF1)/geometry | kb=5.65482E-17; kf=2.0944E-11 |
| RasGDP_NF1 => RasGDP + NF1 | geometry*(kf*RasGDP_NF1-kb*RasGDP*NF1)/geometry | kb=6.28318E-13; kf=2.43474E-11 |
| RasGTP + NF1 => RasGTP_minus_NF1 | geometry*(kf*RasGTP*NF1-kb*RasGTP_minus_NF1)/geometry | kf=6.28318E-13; kb=3.3301E-12 |
| RasGTP_minus_NF1_star_ => RasGDP_minus_NF1_Pi | geometry*(kf*RasGTP_minus_NF1_star_-kb*RasGDP_minus_NF1_Pi)/geometry | kf=1.02102E-11; kb=1.15192E-13 |
| RasGTP_minus_NF1 => RasGTP_minus_NF1_star_ | geometry*(kf*RasGTP_minus_NF1-kb*RasGTP_minus_NF1_star_)/geometry | kb=2.8798E-12; kf=2.18865E-10 |
(added: 22 Mar 2018, 10:51:48, updated: 22 Mar 2018, 10:51:48)