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BIOMD0000000300 - Schmierer2010_FIH_Ankyrins


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Reference Publication
Publication ID: 20955552
Schmierer B, Novák B, Schofield CJ.
Hypoxia-dependent sequestration of an oxygen sensor by a widespread structural motif can shape the hypoxic response--a predictive kinetic model.
BMC Syst Biol 2010; 4: 139
Oxford Centre for Integrative Systems Biology (OCISB), University of Oxford, South Parks Road, Oxford OX1 3QU, UK.  [more]
Original Model: BIOMD0000000300.origin
Submitter: Bernhard Schmierer
Submission ID: MODEL1008170000
Submission Date: 17 Aug 2010 15:36:56 UTC
Last Modification Date: 24 Feb 2015 20:27:07 UTC
Creation Date: 17 Aug 2010 15:11:32 UTC
Encoders:  Bernhard Schmierer
   Vijayalakshmi Chelliah
set #1
bqbiol:hasProperty Human Disease Ontology polycythemia due to hypoxia
set #2
bqbiol:hasProperty Mathematical Modelling Ontology ordinary differential equation model
set #3
bqbiol:isVersionOf Gene Ontology response to oxygen levels
Gene Ontology response to hypoxia
set #4
bqbiol:hasTaxon Taxonomy Homo sapiens

This a model from the article:
Hypoxia-dependent sequestration of an oxygen sensor by a widespread structural motif can shape the hypoxic response - a predictive kinetic model
Bernhard Schmierer, Béla Novák1 and Christopher J Schofield BMC Systems Biology2010, 4:139 20955552,
The activity of the heterodimeric transcription factor hypoxia inducible factor (HIF) is regulated by the post-translational, oxygen-dependent hydroxylation of its α-subunit by members of the prolyl hydroxylase domain (PHD or EGLN)-family and by factor inhibiting HIF (FIH). PHD-dependent hydroxylation targets HIFα for rapid proteasomal degradation; FIH-catalysed asparaginyl-hydroxylation of the C-terminal transactivation domain (CAD) of HIFα suppresses the CAD-dependent subset of the extensive transcriptional responses induced by HIF. FIH can also hydroxylate ankyrin-repeat domain (ARD) proteins, a large group of proteins which are functionally unrelated but share common structural features. Competition by ARD proteins for FIH is hypothesised to affect FIH activity towards HIFα; however the extent of this competition and its effect on the HIF-dependent hypoxic response are unknown.
To analyse if and in which way the FIH/ARD protein interaction affects HIF-activity, we created a rate equation model. Our model predicts that an oxygen-regulated sequestration of FIH by ARD proteins significantly shapes the input/output characteristics of the HIF system. The FIH/ARD protein interaction is predicted to create an oxygen threshold for HIFα CAD-hydroxylation and to significantly sharpen the signal/response curves, which not only focuses HIFα CAD-hydroxylation into a defined range of oxygen tensions, but also makes the response ultrasensitive to varying oxygen tensions. Our model further suggests that the hydroxylation status of the ARD protein pool can encode the strength and the duration of a hypoxic episode, which may allow cells to memorise these features for a certain time period after reoxygenation.
The FIH/ARD protein interaction has the potential to contribute to oxygen-range finding, can sensitise the response to changes in oxygen levels, and can provide a memory of the strength and the duration of a hypoxic episode. These emergent properties are predicted to significantly shape the characteristics of HIF activity in animal cells. We argue that the FIH/ARD interaction should be taken into account in studies of the effect of pharmacological inhibition of the HIF-hydroxylases and propose that the interaction of a signalling sensor with a large group of proteins might be a general mechanism for the regulation of signalling pathways.

There are there models described in the paper. 1) Skeleton Model 1 (SKM1) - HIFα CAD-hydroxylation in the absence of the FIH/AR-interaction. 2) Skeleton Model 2 (SKM2) - FIG sequestration by ARD proteins and oxygen-dependent FIH-release. 3) Full Model (Fusion of SKM1 and SKM2) - the effects of the FIH/ARD proteins interaction on HIFα CAD-hydroxylation.

This model corresponds to the "Full Model" described in the paper. The model reproduces figure 5 of the publication.

This model originates from BioModels Database: A Database of Annotated Published Models ( It is copyright (c) 2005-2011 The Team.
For more information see the terms of use.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Publication ID: 20955552 Submission Date: 17 Aug 2010 15:36:56 UTC Last Modification Date: 24 Feb 2015 20:27:07 UTC Creation Date: 17 Aug 2010 15:11:32 UTC
Mathematical expressions
Htot synthesis Htot basal degradation Htot induced degradation H synthesis
H basal degardation H induced degradation H hydroxylation A synthesis
A degradation A hydroxylation    
Assignment Rule (variable: HOH) Assignment Rule (variable: AOH) Assignment Rule (variable: HP) Assignment Rule (variable: CAD)
Assignment Rule (variable: NAD) Assignment Rule (variable: A for plotting) Assignment Rule (variable: CADOH) Assignment Rule (variable: kdeg_A)
Assignment Rule (variable: ksyn_A) Assignment Rule (variable: KiFH) Assignment Rule (variable: HF) Assignment Rule (variable: FIHfree)
Assignment Rule (variable: KiFA) Assignment Rule (variable: kcatFH)    
Physical entities
Compartments Species
Cell Htot H A
Ftot Ptot HF
HP O2 FIHfree
A for plotting    
Global parameters
alpha KdFH KdFA KdPH
KdHRE gamma kcatPH w
eps kdeg_A ksyn_A KiFH
KiFA kcatFH kdeg_H ksyn_H
Reactions (10)
 Htot synthesis  → [Htot];  
 Htot basal degradation [Htot] → ;  
 Htot induced degradation [Htot] → ;   {Ptot} , {O2} , {HP}
 H synthesis  → [H];  
 H basal degardation [H] → ;  
 H induced degradation [H] → ;   {Ptot} , {O2} , {HP}
 H hydroxylation [H] → ;   {Ftot} , {O2} , {HF}
 A synthesis  → [A];  
 A degradation [A] → ;  
 A hydroxylation [A] → ;   {Ftot} , {O2} , {Atot}
Rules (14)
 Assignment Rule (name: species_4) HOH = species_1-species_2
 Assignment Rule (name: species_6) AOH = species_5-species_3
 Assignment Rule (name: species_10) HP = 0.5*(((species_1-species_8)-parameter_4)+(((parameter_4-species_1)+species_8)^2+4*species_1*parameter_4)^(0.5))
 Assignment Rule (name: species_13) CAD = species_2/(parameter_5+species_1)
 Assignment Rule (name: species_14) NAD = species_1/(parameter_5+species_1)
 Assignment Rule (name: species_16) A for plotting = species_3/species_5
 Assignment Rule (name: species_15) CADOH = (species_1-species_2)/(parameter_5+species_1)
 Assignment Rule (name: parameter_14) kdeg_A = 1/parameter_11
 Assignment Rule (name: parameter_16) ksyn_A = species_5/parameter_11
 Assignment Rule (name: parameter_7) KiFH = parameter_2/parameter_3*(parameter_3+species_3+parameter_6*(species_5-species_3))
 Assignment Rule (name: species_9) HF = 0.5*(((species_2-species_7)-parameter_7)+(((parameter_7-species_2)+species_7)^2+4*species_2*parameter_7)^(0.5))
 Assignment Rule (name: species_12) FIHfree = (parameter_2+species_9)/(parameter_7+species_9)
 Assignment Rule (name: parameter_9) KiFA = parameter_3/parameter_2*(parameter_2+species_9)
 Assignment Rule (name: parameter_13) kcatFH = parameter_8*parameter_10
Functions (5)
 Constant flux (irreversible) lambda(v, v)
 vPH Htot lambda(kcatPH, Ptot, O2, KdPH, Htot, HP, Htot*kcatPH*Ptot*O2/(1+O2)/(KdPH+Ptot+HP))
 vFH lambda(Ftot, O2, alpha, H, KiFH, HF, KcatFH, H*KcatFH*Ftot*O2/(alpha+O2)/(KiFH+Ftot+HF))
 vFA lambda(Ftot, O2, alpha, A, gamma, Atot, KiFA, KcatFH, A*KcatFH*Ftot*O2/(alpha+O2)/(KiFA+A+gamma*(Atot-A)))
 vPH H lambda(H, kcatPH, Ptot, O2, KdPH, HP, H*kcatPH*Ptot*O2/(1+O2)/(KdPH+Ptot+HP))
 Cell Spatial dimensions: 3.0  Compartment size: 1.0
Compartment: Cell
Initial concentration: 0.0
Compartment: Cell
Initial concentration: 0.0
Compartment: Cell
Initial concentration: 100.0
Compartment: Cell
Initial concentration: 0.0
Compartment: Cell
Initial concentration: 100.0
Compartment: Cell
Initial concentration: 0.0
Compartment: Cell
Initial concentration: 1.0
Compartment: Cell
Initial concentration: 0.2
Compartment: Cell
Initial concentration: 0.0
Compartment: Cell
Initial concentration: 0.0
Compartment: Cell
Initial concentration: 0.0
Compartment: Cell
Initial concentration: 0.0099009900990099
Compartment: Cell
Initial concentration: 0.0
Compartment: Cell
Initial concentration: 0.0
Compartment: Cell
Initial concentration: 0.0
   A for plotting
Compartment: Cell
Initial concentration: 1.0
Global Parameters (16)
Value: 0.33   (Units: dimensionless)
Value: 1.0   (Units: dimensionless)
Value: 1.0   (Units: dimensionless)
Value: 1.0   (Units: dimensionless)
Value: 0.3   (Units: dimensionless)
Value: 500.0   (Units: dimensionless)
Value: 1.0   (Units: dimensionless)
Value: 5.0   (Units: dimensionless)
Value: 0.2   (Units: dimensionless)
Value: 20.0   (Units: dimensionless)
Value: 101.0   (Units: dimensionless)
Value: 1.0   (Units: dimensionless)
Value: 500.0   (Units: dimensionless)
Value: 1.0   (Units: dimensionless)
Value: 1.0   (Units: dimensionless)
Representative curation result(s)
Representative curation result(s) of BIOMD0000000300

Curator's comment: (updated: 14 Jan 2011 14:35:50 GMT)

Figure 5 of the publication has been reproduced here. Figure 5As are generated by varying the amount of ARD proteins (Atot) from 0 to 500, keeping gamma = 0 and epsilon = 5. Figure 5Bs are generated by varying gamma, the binding affinities of FIH for hydroxylated ankyrin repeats from 0 to 0.1, keeping Atot = 100 and epsilon = 5. Figure 5Cs are generated by varying epsilon, the timescale of basal HIF? turnover relative to the timescale of ARD protein turnover from 1 to 10, keeping Atot = 100 and gamma = 0.02. The model was integrated and simulated using Copasi v4.6 (Build 32).