Structure and function of E3 ligase complexes in immune signalling regulation

E3 ligases perform the final step of an enzyme cascade reaction where ubiquitin, or ubiquitin-like molecules, are covalently attached to substrates. Understanding the structural basis of how these E3 ligase complexes assemble and modify substrates is key to ongoing efforts to study their roles in biology. The UFL1 E3 ligase complex catalyses the transfer of the ubiquitin-like molecule UFM1 and UFMylates ribosomes. I present the cryo-EM structure of the UFL1 E3 ligase complex bound to the 60S ribosome, which shows how this three-subunit ligase complex is poised to transfer UFM1 onto the 60S protein RPL26. The ligase obstructs the tRNA binding sites at one end and SEC61/peptide exit tunnel at the other end. Additionally, a long UFL1 loop extends into the peptidyl transferase centre (PTC), acting as a potential sensor of PTC occupancy status. The intricate interactions between the ligase complex and multiple ribosomal proteins provide a rationale for UFM1 modifications in regulating ribosome quality control. Collectively, these results provide a long- awaited structural mechanism for UFM1 transfer and lay the groundwork for investigating the mechanism of action and biological relevance of ribosome UFMylation.