Publication highlights

The modification of proteins with a small regulatory protein called ubiquitin influences the majority of cellular functions and malfunction is implicated in many diseases. To capitalise on the therapeutic potential of regulating ubiquitination processes, we need to understand the mechanisms of the enzymes that catalyse it: E3 ubiquitin ligases. Researchers at the Crick characterise a previously unrecognised sub-family of ‘pseudoligases’, which lack key structural and catalytic features. These deviations mean that they cannot catalyse ubiquitination but instead appear to regulate active E3 ligases. Uncovering this unexpected evolutionary strategy takes us a step closer to understanding and manipulating the ubiquitin system.

Small molecule probes offer powerful tools for the study of biological systems and can serve as starting points for the development of therapeutics. The vast majority of human proteins lack such chemical tools, which hinders our ability to explore their function in the context of health and disease. Screening libraries of “reactive fragments”, small molecules that form covalent bonds with their protein targets, by mass spectrometry enables the discovery of new ligands in the native cellular environment. Together with GSK as part of the Crick-GSK Biomedical LinkLabs Prosperity Partnership, researchers at the Crick have developed a robust and versatile proteomics platform for profiling of cysteine-reactive fragments against the native proteome and have identified hundreds of new protein-ligand interactions for probe development.

TRIM proteins constitute a protein family with highly diverse functions but a common architectural feature, the TRIM or RBCC motif. TRIM2 and TRIM3 are expressed mainly in the brain and regulate different neuronal functions. In this paper, the Rittinger lab describes a detailed structure function analysis of TRIM2 and TRIM3, which despite high sequence identity, exhibit very different properties. TRIM2 and TRIM3 are both expressed in the brain but their expression levels in different cell types are not equivalent: TRIM2 is mainly present in the corpus callosum whilst TRIM3 is mostly found in the cerebellum. The corpus callosum plays a role in spatial and sensory coordination by connecting the two brain hemispheres through a large fibre tract and it is an exclusive feature of the placental brain. This raises the fascinating hypothesis that perhaps the divergence of TRIM2 and TRIM3 contributed to the acquisition of higher functions of an evolving brain.