Cells in the human body must quickly respond to countless challenges like changes in the environment, damage to cellular components or infections by changing their internal signalling pathways. Cells do this by modifying or degrading existing proteins by attaching small markers (post-translational modifications). The small protein ubiquitin is one such marker and is attached by enzymes called E3 ubiquitin ligases.
The human genome encodes for more than 700 E3 ubiquitin ligases that each act on very specific targets and regulate fundamental cellular processes. Their importance for cellular health is underscored by the fact that mutations in E3 ligases can cause a vast range of human diseases such as inflammation, cancer, and autoimmune or neurodegenerative diseases. E3 ligases are thus new targets for innovative treatment options in these conditions.
We study E3 ubiquitin ligases to understand their functions in the human body, their roles in human diseases and to lay the groundwork for drug discovery to target these diseases.
Our most recent impact is in understanding the catalytic mechanism of the RBR E3 ubiquitin ligase family and its allosteric regulation by ubiquitin chains. In the past few years, we have contributed many key insights into these processes (Lechtenberg et al., Nature 2016; Cotton et al. Molecular Cell 2022; Wang & Cotton et al, Nature Communications 2023).
We are now able to leverage these molecular insights to investigate the biological functions of this enzyme family, including how mutations in the RBR E3 ligase RNF216 leads to the neurodegenerative disease Gordon Holmes Syndrome.
RBR E3 ubiquitin ligases are highly regulated enzymes that are generally found in an autoinhibited conformation and are only activated upon specific upstream signals. They use a distinct 2-step catalytic mechanism and contain an active site in their RING2 domain.
In the last few years, we have made vast progress on unravelling the general catalytic mechanism and regulation of the RBR E3 ubiquitin ligase family, e.g., Lechtenberg et al., 2016, Nature; Cotton et al. Molecular Cell 2022, Wang & Cotton et al, Nature Communications 2023.
Some of the RBR E3 ubiquitin ligases are part of larger complexes.
For example, the ligase HOIP is part of the linear ubiquitin chain assembly complex (LUBAC). LUBAC is a regulator of innate immunity and cell death downstream of the TNF receptor and has been linked to autoimmune diseases and inflammation.
We study the composition of these complexes and how they affect E3 ligase activity. We aim to solve the structure of these complexes using X-ray crystallography and cryo-electron microscopy, which will provide functional insights and guide development of small molecules that target these E3 ligase complexes.
Many of the 14 members of the RBR family in humans have not been well studied, and we do not appreciate their important cellular functions.
We use mass spectrometry and cell biology in conjunction with biochemistry and structural biology to unravel the signalling networks of these enzymes.
Our goal is to develop annotated interaction networks of specific RBR E3 ligases and identify their substrates, cofactors, and upstream regulators. This will provide comprehensive novel insights into their biological and pathophysiological roles.
We further aim to develop probes and inhibitors for specific E3 ligases as research tools and leads for drug development.
E3 ubiquitin ligases are often highly specific enzymes that regulate fundamental cellular functions and thus are involved in many human diseases such as inflammation, cancers, and neurodegenerative diseases including Parkinson’s disease. E3 ligases therefore constitute novel therapeutic targets in treating these diseases.
In addition, certain E3 ligases induce the degradation of specific proteins. This activity can be hijacked and directed towards other, disease-causing proteins using bivalent small molecule drugs known as targeted protein degrader drugs.
Together with other researchers at WEHI and in Australia, including medicinal chemists, biologists, and clinicians, we aim to develop small molecule probes and drug candidates that bind E3 ligases. These small molecules may be used as direct E3 ligase inhibitors, or as E3 ligase recruiters in targeted protein degrader drugs.
The Lechtenberg lab is a multidisciplinary team that combines structural biology with biochemistry, cell biology, and mass spectrometry.
We closely collaborate with other laboratories in the Ubiquitin Signalling division and WEHI. We are always interested to hear form enthusiastic candidates at all career stages who share our love for all things ubiquitin and E3 ubiquitin ligases.