Khan, Mohammad Farhan (2017) Robustness and Responsiveness in Eukaryotic Protein Synthesis. Doctor of Philosophy (PhD) thesis, University of Kent,. (doi:10.22024/UniKent/01.02.63887) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:63887)
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Official URL: https://doi.org/10.22024/UniKent/01.02.63887 |
Abstract
Phosphorylation of eukaryotic translation initiation factor 2 (eIF2) is one of the best studied and most widely used means for regulating protein synthesis activity in eukaryotic cells. Control through eIF2 is exerted by its phosphorylation, which disrupts the guanidine exchange cycle that is required for every initiation event, and thereby inhibits translation. The eIF2 pathway regulates protein synthesis in response to stresses, viral infections, and nutrient depletion, among others. We present analyses of an ordinary differential equation-based model of this pathway, which aim to identify its principal robustness and stability conferring features using linear control theory. The eIF2 pathway can respond sensitively, appropriately and in a timely fashion to some changes in the environment of the cell, while being robust and unresponsive to other types of change. Neither the way in which appropriate responses are achieved (responsiveness), nor how inappropriate responses are avoided (robustness), is currently well understood.
Our analyses indicate that, within eIF2 dependent regulatory model the robustness do not arising from the properties of any one individual pathway species rather is a distributed property. On the other hand, stability lies in the structure of the model that is damaging the structure produces major alterations in the stability. Further it is observed that, key non-linearities within the system helps in maintaining transient behaviour and removal or linearisation of key non-linearities can generate undesirable results such as negative cellular concentration. Our analyses also indicate existence of natural sliding surface within the eIF2 dependent regulatory system that helps the system in counteracting uncertainties lies in the input channel. Further, the role of uncharged transfer ribonucleic acid (tRNA) and protein kinase R (PKR) signalling on general translation rate as well as on phosporylation of eIF2-alpha is also investigated by extrapolating the proposed computational yeast model to the case of mammalian cells. It is observed that PKR is compensating the loss of general control nonderepressible 2 (GCN2) and maintaining levels of phosphorylated eIF2-alpha in tumours, while signalling strength of uncharged tRNA is responsible for delivering statistically significant difference in the ratio of phosphorylated eIF2 and alpha-subunit of eIF2 for mixed background and C57BL6 sarcomas.
Item Type: | Thesis (Doctor of Philosophy (PhD)) |
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Thesis advisor: | Yan, Xinggang |
Thesis advisor: | von der Haar, Tobias |
Thesis advisor: | Spurgeon, Sarah K. |
DOI/Identification number: | 10.22024/UniKent/01.02.63887 |
Additional information: | The author of this thesis has requested that it be held under closed access. We are sorry but we will not be able to give you access or pass on any requests for access. 22/06/21 |
Uncontrolled keywords: | Protein synthesis, mathematical model, eukaryotic initiation factor 2 dependent regulatory system, general control nonderepressible 2, stability and robustness analyses, non-linear system, linearisation, control application, computational biology. |
Divisions: | Divisions > Division of Computing, Engineering and Mathematical Sciences > School of Engineering and Digital Arts |
SWORD Depositor: | System Moodle |
Depositing User: | System Moodle |
Date Deposited: | 06 Oct 2017 13:59 UTC |
Last Modified: | 20 Jul 2021 09:21 UTC |
Resource URI: | https://kar.kent.ac.uk/id/eprint/63887 (The current URI for this page, for reference purposes) |
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