Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

Corbett, Michael S. P. (2017). Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors PhD Thesis, School of Chemistry and Molecular Biosciences, The University of Queensland. doi:10.14264/uql.2017.333

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Author Corbett, Michael S. P.
Thesis Title Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors
School, Centre or Institute School of Chemistry and Molecular Biosciences
Institution The University of Queensland
DOI 10.14264/uql.2017.333
Publication date 2017-02-10
Thesis type PhD Thesis
Supervisor Alan E. Mark
David Poger
Total pages 149
Language eng
Subjects 0202 Atomic, Molecular, Nuclear, Particle and Plasma Physics
0307 Theoretical and Computational Chemistry
0601 Biochemistry and Cell Biology
Formatted abstract
The ability of a cell to recognise and respond to external stimuli is essential for cell survival and growth. Type-I cytokine receptors regulate many inflammatory, homeostatic, and growth and development signalling pathways. For example, the erythropoietin receptor is the main driver of red blood cell production from stem cells. All type-I cytokine receptors consist of an extracellular ligand-binding domain, a single helical transmembrane domain and an intracellular domain that associates with kinase/transcription factor signalling pathway, for example the JAK2/STAT5 pathway. Despite being extensively studied and structures of the extracellular domains of many of these receptors being known, the precise mechanism by which these receptors couple the event of ligand-binding to intracellular activation is not known. Indeed, multiple mechanisms have been proposed from experimental and crystallographic data for different receptors. For example, the activation of the growth hormone receptor is proposed to involve a relative rotation of two receptor chains, while in the case of the erythropoietin receptor the chains were suggested to separate in a scissor-like mechanism. In part, this is due to the limits of resolution achievable by experimental approaches as well as a lack of appreciation for the dynamical properties of the receptor proteins and the membrane environment. This thesis focuses on the use of fully atomistic molecular dynamics simulations to investigate the mechanism of activation for the type-I cytokine receptors. In particular MD simulations are used to probe whether conformations of the receptors observed crystallographically are representative of physiological conformations. Further to this, the quality of the X-ray crystal structures is tested by recreation of the crystal lattice in MD simulations. The effect of membrane composition is investigated by comparing the behaviour of the transmembrane domain in bulk and cholesterol-enriched raft-like bilayers. Finally, receptor dimers are examined for active and inactive conformations in raft-like bilayers containing sphingomyelin. Force field parameters for the lipid sphingomyelin that were used to build raft-like bilayers were also generated and validated. The work draws into question several of the mechanistic models proposed for the type-I cytokine receptors and demonstrates the difficulty in proposing a detailed mechanism of action based on limited sets of structural data. In particular, they highlight the limitations of the use of structural data in proposing a model when only a part of the receptor is considered. Results from the simulations also suggest that the lipid composition can influence the structure and behaviour of the receptors. Taken together the work shows the importance of considering not only the ligand-binding domain of the receptor but also the restrictions imposed by the transmembrane domain and structural influences caused by the membrane when proposing a mechanism of activation for this important class of cell surface receptor.
Keyword Cytokine
Erythopoietin
Growth hormone
Receptor
Signalling
Molecular dynamics
Sphingomyelin
Lipid rafts

Document type: Thesis
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Created: Wed, 08 Feb 2017, 15:38:14 EST by Michael Corbett on behalf of Learning and Research Services (UQ Library)