Hasan, Muhammad (2015) An NMR study into the structure and interactions of the transmembrane domains of Neu and PDGFβ receptor tyrosine kinases. PhD thesis, University of Warwick.

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Abstract

Receptor tyrosine kinases (RTKs) form a medically important class of membrane proteins whose malfunction as signalling entities has been reported as the cause of a large number of diseases. The structure and dynamics of the transmembrane domain (TM) of these receptors is central to their role in cellular signalling. However, this structure–function relationship is poorly understood. This is largely due to the problems associated with the production of these proteins for analyses in vitro and the fact that they are hydrophobic and require membrane mimetics to solubilise them, which in turn often means loss of structural integrity.

This study aimed at using solution- and solid- state NMR to probe the structure and interactions of two biologically important RTK-TMs for which no high resolution structures exist. For the oncogenic Neu receptor tyrosine kinase transmembrane domain, it was sought to understand which amino acids are involved in stabilising the helical dimer. Synthetic peptides were reconstituted into liposomes and then analysed using solid-state NMR. The platelet-derived growth factor β receptor transmembrane domain was another RTK-TM whose structure and interactions with E5 protein were studied using solution-state NMR. A detailed protocol for the expression, purification and reconstitution of PDGFβR-TM into membrane mimetics was devised in order to perform the stated NMR analyses.

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QP Physiology
Library of Congress Subject Headings (LCSH):	Protein-tyrosine kinase, Cell membranes
Official Date:	August 2015
Dates:	Date Event August 2015 Submitted
Institution:	University of Warwick
Theses Department:	Molecular Organisation and Assembly in Cells
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Dixon, Ann M. ; Lewandowski, Józef R. ; Brown, Steven P. ; Allen, M. P.
Sponsors:	Engineering and Physical Sciences Research Council (EPSRC)
Extent:	xv, 216 leaves : illustrations
Language:	eng

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