Structural investigation of E3 ubiquitin ligases in innate immune signalling

• Honours
• PhD

This project builds on long-standing research in the Lechtenberg lab investigating the structure and mechanism of a specific family of E3 ubiquitin ligases, the RING-between-RING (RBR) ligases (Lechtenberg, Nature 2016, 529(7587):546; Cotton, Mol. Cell 2022, 82(3):598; Wang, Nat Comms 2023, 14(1):168; Wang, Life Sci. Alliance 2025, 8(6)).

In this project, students will focus on the linear ubiquitin chain assembly complex (LUBAC) and its E3 ubiquitin ligase components HOIP and HOIL-1. LUBAC plays a central role in regulating innate immune and cell death signalling downstream of the TNFalpha receptor.

Students will learn core skills in recombinant protein expression and purification (bacterial and mammalian cells), biochemical characterisation of E3 ubiquitin ligases and structural biology (X-ray crystallography and cryo-EM).

The Lechtenberg lab investigates E3 ubiquitin ligases, enzymes that catalyse a cellular process termed ubiquitination. E3 ubiquitin ligases are molecular label makers that attach the small protein ubiquitin to other proteins to induce protein degradation or regulate protein activity, subcellular localisation or interactions with other proteins.

Ubiquitination provides a diverse signalling code and regulates almost all processes inside the human cell and is a central player in human physiology and disease.

Our research provides the molecular basis for E3 ubiquitin ligase activity and regulation and aims to transfer these insights to the cellular function of the E3s ligases, for example in ribosomal quality control, innate immune signalling or cancer. Our lab utilises a combination of structural (crystallography, cryo-EM), biophysical, biochemical and cell biological methods.