Biochemical and cellular characterisation of disease-associated Developmentally Regulated GTP-binding proteins

Westrip, Christian Alexander Edward (2023). Biochemical and cellular characterisation of disease-associated Developmentally Regulated GTP-binding proteins. University of Birmingham. Ph.D.

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Abstract

GTPases are a large superfamily of proteins that are capable of binding guanosine triphosphate (GTP) and hydrolysing it into guanosine diphosphate (GDP). The Developmentally Regulated GTP-binding proteins 1 and 2 (DRG1 and DRG2) are both highly conserved GTPases implicated in fundamental cellular processes, such as microtubule regulation and protein synthesis. In addition, both DRG1 and DRG2 have conserved binding partners: DRG family regulatory protein 1 and 2 (DFRP1 and DFRP2), respectively. Despite their high conservation and links to important cellular functions, DRGs and DFRPs have remained poorly characterised in normal cellular physiology and in disease. Here, I investigate the biochemical and cellular functions of theses GTPases and their DFRP binding partners. I begin by characterising the binding specificity between DRGs and DFRPs, including the identification of residues in DRG1 that might be important for specifying DFRP1 binding. I next characterise an interaction between the DRG1/DFRP1 complex and the Muf1 E3 ubiquitin ligase. I also provide evidence supporting a role for both DRG1 and DRG2 in promoting efficient translation elongation through poly-basic encoding sequences. Finally, I show evidence that pathogenic variants in DRG1 interfere with GTPase activity and DFRP1 binding in patients affected by a novel neurodevelopmental disorder. Overall, the findings establish new and exciting areas of research for DRGs.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):