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Bernhard Lechtenberg-Projects
Researcher:
Catalytic mechanism and regulation of RBR E3 ubiquitin ligases
RBR E3 ubiquitin ligases are considered 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.
Despite recent progress by our team (Lechtenberg et al., 2016, Nature) and other labs, many open questions still remain for many of the RBRs:
- How are RBR E3 ligases retained in their autoinhibited conformation?
- How are they activated and what conformational changes are necessary?
- What residues and features are critical for their E3 ligase activity?
Different RBR ligases are activated by distinct mechanisms (such as cofactor binding, phosphorylation, dimerization) and via binding of an allosteric ubiquitin (or ubiquitin-like; UBL) molecule (Steps 1 and 2).
Activated RBR E3 ligases can enter the catalytic cycle and ubiquitinate their substrates.
Structure and function of RBR E3 ubiquitin ligase complexes
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 ultimately 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.
HOIP, HOIL-1L, and Sharpin interact via their UBA and UBL domains to form the LUBAC.
Binding sites for other known regulatory proteins, substrates, and cofactors are indicated.
RBR E3 ubiquitin ligase signalling networks
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.
All RBR ligases share the RBR E3 ligase module but show a high degree of diversity outside the RBR, reflecting their distinct modes of regulation and interactions with other proteins such as cofactors and substrates.
RBR E3 ubiquitin ligases as drug targets
RBR E3 ubiquitin ligases are tightly controlled 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. RBR ligases may thus constitute novel therapeutic targets in treating these diseases.
Together with other researchers at the Institute, including medicinal chemists and biologists, we aim to develop small molecule probes and drug candidates that bind RBR E3 ligases.
Our approaches include directly targeting the active site and utilising the complex regulatory mechanisms of the RBR E3 ligases in order to inhibit or activate them, depending on the disease model.