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Model Identifier
BIOMD0000000300
Short description
Format
SBML
(L2V4)
Related Publication
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Hypoxia-dependent sequestration of an oxygen sensor by a widespread structural motif can shape the hypoxic response--a predictive kinetic model.
- Bernhard Schmierer, Béla Novák, Christopher J Schofield
- 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.
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.
Contributors
Submitter of the first revision: Bernhard Schmierer
Submitter of this revision: Bernhard Schmierer
Curator: Lucian Smith
Modeller: Bernhard Schmierer
Submitter of this revision: Bernhard Schmierer
Curator: Lucian Smith
Modeller: Bernhard Schmierer
Metadata information
Curation status
Curated
Modelling approach(es)
Connected external resources
SBGN view in Newt Editor
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| Name | Description | Size | Actions |
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Model files (1) |
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| BIOMD0000000300.xml.origin | SBML L2V4 representation of Schmierer2010_FIH_Ankyrins | 29.18 KB | Preview | Download |
- Model originally submitted by : Bernhard Schmierer
- Submitted: Aug 17, 2010 3:36:56 PM
- Last Modified: Aug 21, 2024 8:42:53 PM
Revisions
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Version: 3
- Submitted on: Aug 21, 2024 8:42:53 PM
- Submitted by: Lucian Smith
- With comment: CRBM-sponsored manual and automated updates.
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Version: 2
- Submitted on: Feb 24, 2015 8:27:07 PM
- Submitted by: Bernhard Schmierer
- With comment: Current version of Schmierer2010_FIH_Ankyrins
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Version: 1
- 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 of this model will only be shown to the submitter and their collaborators.
Curator's comment:
(added: 14 Jan 2011, 14:35:50, updated: 14 Jan 2011, 14:35:50)
(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).