Project title: Understanding the inhibition mechanism of N4BP1 on the linear ubiquitin E3 ligase complex LUBAC
Summary: The linear ubiquitin assembly complex LUBAC is a ubiquitin E3 ligase with crucial roles in the initiation of the innate immune response and the activation of the NF-κB signaling pathway. Dysregulation of LUBAC is associated with autoinflammation, immunodeficiencies and the development of diffuse large B-cell lymphoma (DLBCL). LUBAC displays the unique feature to generate so called linear ubiquitin chains. In contrast to any other type of ubiquitin chains, linear or M1-linked ubiquitin chains are formed via a peptide bond between the C-terminal glycine and the N-terminal methionine of two adjacent ubiquitin molecules. It has been shown that the synthesis and attachment of linear ubiquitin chains to key elements of the NF-κB pathway are a prerequisite for its activation. To date LUBAC is the only known enzyme, which can mediate these functions. Currently the ligase complex is extensively investigated to explore its therapeutic potential, in particular for the development as an anti-cancer drug target for patients with DLBCL. N4BP1 is a novel type of linear ubiquitin receptor that inhibits LUBAC by modulating both its E3 ligase activity and substrate recruitment under pro-inflammatory conditions.
This project will employ structural biology, biochemical and biophysical methods to elucidate (1) how N4BP1 inhibits LUBAC and (2) how N4BP1 binds and recognizes linear ubiquitin chains with high specificity.