Two different representations of tetra-ubiquitin - a molecular 'tag' used to mark proteins inside cells.

Katrin Rittinger : Areas of interest

Introduction

The modification of proteins with the small molecule ubiquitin regulates a large variety of cellular processes. We are particularly interested in the role of ubiquitination in the regulation of immune and inflammatory signalling pathways.

LUBAC is a multi-subunit RBR E3 ligase that synthesizes linear ubiquitin chains with high specificity.

Figure 1: LUBAC is a multi-subunit RBR E3 ligase that synthesizes linear ubiquitin chains with high specificity. The structure of the active HOIP-ubiquitin transfer complex shown here explains how the LUBAC subunit HOIP recognises the donor and acceptor ubiquitin and determines chain linkage specificity.

We are employing a broad array of structural, biochemical and biophysical approaches to gain insight into the protein machinery and regulatory mechanisms mediating the ubiquitination process.

Ubiquitination is a versatile post-translational modification that regulates a large variety of cellular processes including signalling networks that mediate immune and inflammatory responses. The functional outcome of the modification depends on the type of ubiquitin signal generated and proteins can become modified with individual ubiquitin molecules or with polyubiquitin chains that are formed by conjugation of ubiquitin molecules via one of their seven lysine residues or the N-terminal methionine. Modification of proteins with ubiquitin depends on the sequential activity of three enzymes, the last of which are E3 ubiquitin ligases that select the substrate to be modified and in some cases also determine the type of polyubiquitin chain that will be synthesised.

Our research is focused on the characterisation of the mechanism of two different families of E3 ubiquitin ligases, the RBR (RING-Between-RING) family and the TRIM (tripartite motif) family using a combination of structural, biochemical and biophysical approaches. Members of both of these E3 families have been shown to play important regulatory roles in immune and inflammatory signalling and defects in their activity have been linked to a number of diseases.

Figure 1: LUBAC is a multi-subunit RBR E3 ligase that synthesizes linear ubiquitin chains with high specificity. The structure of the active HOIP-ubiquitin transfer complex shown here explains how the LUBAC subunit HOIP recognises the donor and acceptor ubiquitin and determines chain linkage specificity.(Click to view larger image)