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Title: Structural and biochemical characterisation of the HR1 domains of the protein kinase C-related kinase family
Author: Sophocleous, Georgios
ISNI:       0000 0004 7961 9315
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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The Rho family of small GTPases act as molecular switches in the cell and are involved in signalling pathways implicated in cytoskeletal organisation. To mediate their effects, they interact with downstream effectors. The protein kinase C-related kinase (PRK) family of serine/threonine kinases consists of three members, PRK1, PRK2 and PRK3, all of which are Rho family effectors. PRKs have three N-terminal Homology Region 1 (HR1) domains, HR1a, HR1b and HR1c. These are predicted antiparallel coiled coils which interact with the Rho proteins. While HR1a and HR1b domains have been studied in vitro, very little is known about the HR1c domain. This project aims to provide much-needed biochemical, biophysical and structural understanding of HR1 domains. The secondary structure and stability of PRK1 and PRK3 HR1 domains is outlined, followed by the identification of some HR1 domains as oligomerisation domains of their respective PRK. Analysis of the oligomeric state of the single, di- and tri-domains indicates that the three HR1 domains are not independent in solution. The NMR solution structure of the PRK1 HR1c domain is solved, highlighting the differences between this domain and other HR1 domains. The structure is then used as a tool to delineate the interactions between the three PRK1 HR1 domains. A model is created which summarises intra- and inter-molecular HR1 interactions. GTPase-HR1 interactions then expand the model by linking the HR1 oligomerisation to GTPase binding. New GTPase interactions with PRK1 and PRK3 HR1 domains are also identified, highlighting our limited knowledge about the PRKs and the subsequent studies which will need to follow.
Supervisor: Mott, Helen Sponsor: A.G. Leventis Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: PRK ; PRK1 ; RhoA ; GTPase ; HR1 ; G protein ; Rho ; PKN ; HR1a ; HR1b ; HR1c ; Structure ; Interactions