Schmierer2010_FIH_Ankyrins

  public model
Model Identifier
BIOMD0000000300
Short description

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,
Abstract:
Background
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.
Results
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.
Conclusions
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 (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net 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.

Format
SBML (L2V4)
Related Publication
  • Hypoxia-dependent sequestration of an oxygen sensor by a widespread structural motif can shape the hypoxic response--a predictive kinetic model.
  • Schmierer B, Novák B, Schofield CJ
  • BMC systems biology , 10/ 2010 , Volume 4 , pages: 139 , PubMed ID: 20955552
  • Oxford Centre for Integrative Systems Biology (OCISB), University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
  • 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.
Contributors
Bernhard Schmierer

Metadata information

is
BioModels Database MODEL1008170000
BioModels Database BIOMD0000000300
isDescribedBy
PubMed 20955552
hasTaxon
Taxonomy Homo sapiens
isVersionOf
Gene Ontology response to hypoxia
Gene Ontology response to oxygen levels
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
Human Disease Ontology polycythemia due to hypoxia

Curation status
Curated


Tags
Name Description Size Actions

Model files

BIOMD0000000300_url.xml SBML L2V4 representation of Schmierer2010_FIH_Ankyrins 45.75 KB Preview | Download

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BIOMD0000000300.svg Auto-generated Reaction graph (SVG) 27.83 KB Preview | Download
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BIOMD0000000300.pdf Auto-generated PDF file 211.14 KB Preview | Download
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BIOMD0000000300_urn.xml Auto-generated SBML file with URNs 45.10 KB Preview | Download
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  • Model originally submitted by : Bernhard Schmierer
  • Submitted: Aug 17, 2010 3:36:56 PM
  • Last Modified: Feb 24, 2015 8:27:07 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Feb 24, 2015 8:27:07 PM
    • Submitted by: Bernhard Schmierer
    • With comment: Current version of Schmierer2010_FIH_Ankyrins
  • Version: 1 public model Download this version
    • Submitted on: Aug 17, 2010 3:36:56 PM
    • Submitted by: Bernhard Schmierer
    • With comment: Original import of Schmierer_FIH_Ankyrins

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
species 1

Endothelial PAS domain-containing protein 1 ; Hypoxia-inducible factor 1-alpha ; Hypoxia-inducible factor 3-alpha
0.0 dimensionless
species 2

Endothelial PAS domain-containing protein 1 ; Hypoxia-inducible factor 1-alpha ; Hypoxia-inducible factor 3-alpha
0.0 dimensionless
species 3

Ankyrin-1
100.0 dimensionless
species 4

Hypoxia-inducible factor 1-alpha ; Endothelial PAS domain-containing protein 1 ; Hypoxia-inducible factor 3-alpha
0.0 dimensionless
species 6

Ankyrin-1
0.0 dimensionless
species 9 0.0 dimensionless
species 10 0.0 dimensionless
species 12 0.0099009900990099 dimensionless
Reactions
Reactions Rate Parameters
=> species_1 compartment_1*parameter_18 parameter_18 = 1.0 dimensionless
species_1 => compartment_1*parameter_17*species_1 parameter_17 = 1.0 dimensionless
species_1 => ; species_8, species_11, species_10 compartment_1*species_1*parameter_8*species_8*species_11/(1+species_11)/(parameter_4+species_8+species_10) parameter_8 = 500.0 dimensionless; parameter_4 = 1.0 dimensionless
=> species_2 compartment_1*parameter_18 parameter_18 = 1.0 dimensionless
species_2 => compartment_1*parameter_17*species_2 parameter_17 = 1.0 dimensionless
species_2 => ; species_8, species_11, species_10 compartment_1*species_2*parameter_8*species_8*species_11/(1+species_11)/(parameter_4+species_8+species_10) parameter_8 = 500.0 dimensionless; parameter_4 = 1.0 dimensionless
species_2 => ; species_7, species_11, species_9 compartment_1*species_2*parameter_13*species_7*species_11/(parameter_1+species_11)/(parameter_7+species_7+species_9) parameter_7 = 101.0 dimensionless; parameter_1 = 0.33 dimensionless; parameter_13 = 500.0 dimensionless
=> species_3 compartment_1*parameter_16 parameter_16 = 20.0 dimensionless
species_3 => compartment_1*parameter_14*species_3 parameter_14 = 0.2 dimensionless
species_3 => ; species_7, species_11, species_5 compartment_1*species_3*parameter_13*species_7*species_11/(parameter_1+species_11)/(parameter_9+species_3+parameter_6*(species_5-species_3)) parameter_1 = 0.33 dimensionless; parameter_9 = 1.0 dimensionless; parameter_13 = 500.0 dimensionless; parameter_6 = 0.0 dimensionless
species_4 = species_1-species_2 [] []
species_6 = species_5-species_3 [] []
species_9 = 0.5*(((species_2-species_7)-parameter_7)+(((parameter_7-species_2)+species_7)^2+4*species_2*parameter_7)^(0.5)) [] parameter_7 = 101.0 dimensionless
species_10 = 0.5*(((species_1-species_8)-parameter_4)+(((parameter_4-species_1)+species_8)^2+4*species_1*parameter_4)^(0.5)) [] parameter_4 = 1.0 dimensionless
species_12 = (parameter_2+species_9)/(parameter_7+species_9) [] parameter_7 = 101.0 dimensionless; parameter_2 = 1.0 dimensionless
Curator's comment:
(added: 14 Jan 2011, 14:35:50, updated: 14 Jan 2011, 14:35:50)
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).