Late pupal visual system

This project is now closed

Structural and functional characterisation of ubiquitin-dependent signalling processes in immunity

Project supervisor: Katrin Rittinger (Molecular Structure)

Research in our group is aimed at the structural and functional characterisation of proteins that regulate immune signalling pathways in a ubiquitin-dependent fashion. Ubiquitin is a small 76 amino acid protein that can be attached to lysine residues of target proteins or other ubiquitin molecules to form ubiquitin chains and thereby regulate a wide range of cellular functions including protein degradation, proliferation, DNA repair and immune responses. The physiological response induced upon modification of a protein with ubiquitin depends on the way ubiquitin molecules are linked: ubiquitin contains 7 lysine residues which can be linked to the C-terminus of another ubiquitin molecule to form a chain. In addition, the C-terminus of one ubiquitin molecule can be linked to the N-terminal methionine of another to produce a type of chain called "linear ubiquitin chain".

Modification of a target protein with ubiquitin is catalysed by a cascade of 3 enzymes including E1 activating enzymes, E2 conjugating enzymes and E3 ubiquitin ligases. E3 ligases are responsible for selection of the protein substrate and in some cases for determining what type of ubiquitin chain is being formed. This project is aimed at elucidating how certain types of E3 ligases catalyse the formation of specific types of polyubiquitin chains and how this activity is regulated.

To study these processes we are using a multi-disciplinary approach combining structural, biophysical and biochemical methods. These involve molecular biology methods to produce plasmids that allow high level expression of recombinant proteins in bacteria and eukaryotic systems. After successful purification of the proteins of interest, their activity and interaction with binding partners will be analysed using a range of complementary structural, biochemical and biophysical methods. This project is ideally suited for students who would like to gain experience in protein biochemistry and modern structural biology.

Schematic of the ubiquitination cascade

Schematic of the ubiquitination cascade

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The reaction starts with the ATP-dependent formation of a E1-ubiquitin thioester, via E2 conjugation enzymes and E3 ligases to a protein substrate (yellow hexagon) to induce a specific cellular response.

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