Posttranslational modifications of the tumor suppressor PTCH1: characterisation and functional significance

Supervisor(s)

Dr Natalia Riobo-Del Galdo

Prof. Richard Bayliss

Project description

PTCH1, the receptor of the Hedgehog family of proteins and a well-characterised tumor suppressor, is a 12-transmembrane protein with long intracellular N- and C-termini (1). Our lab has developed a particular interest in the C-terminal domain (CTD), which regulates protein turnover, self-oligomerisation, and initiates anticancer signalling through interaction with a growing number of proteins. We recently published two articles describing the interaction of PTCH1 CTD with the ubiquitin ligase ITCH, leading to its ubiquitylation (2) and with the autophagy regulatory protein ATG101 (3). We are currently characterising the protein-protein interaction regions and the structural features of the CTD of PTCH1.

The CTD of PTCH1 is predicted to be mostly unstructured and may only adopt an ordered conformation upon binding to other proteins. Several phosphorylation sites lie within the CTD, and we anticipate that this will influence its structure and interactions. Indeed, phosphorylation might cause the CTD to adopt a helical conformation, a mechanism that we recently discovered as the basis for the formation of a microtubule-associated complex (4).

This PhD project will characterise and investigate the role of phosphorylation of the CTD on its known functions. It will employ methods in mammalian and bacterial expression systems, biochemistry, molecular biology and structural biology to:

1-         Characterise the kinase(s) involved in phosphorylation of the proximal region of the CTD

2-         Investigate the structural changes of the CTD caused by phosphorylation

3-         Investigate the functional consequences of CTD phosphorylation

The successful candidate will preferably have experience in biochemistry and structural biology methods.

Entry requirements

Candidates should have, or be expecting, a 2.1 hons at Undergraduate level or above, in a relevant subject. If English is not your first language, you will need a recognised English Language qualification to be admitted onto any of the University's degree programmes: language requirements https://www.leeds.ac.uk/info/123100/admissions/143/entry_requirements

How to apply

Please apply online

Please include supervisor name and project title.  A research proposal is not required.  Please upload a CV and transcripts.

How to apply (email)

fbsgrad@leeds.ac.uk

How to apply (phone)

+44 (0)113 343 8186