Deciphering the mechanisms of protein modifications by UFM1

The extent of the importance of protein modification by UFM1 (ufmylation) has become appreciated over the last few years. This modification plays a role in crucial cellular processes, including protein unfolding and DNA damage responses. Similar to ubiquitin, a three-enzyme cascade involving E1, E2 and E3 is required to attach UFM1 to the target protein. However, a detailed mechanistic understanding of these enzymes is still missing. I will present our latest findings on the UFM1 E2 enzyme, UFC1, and the E3 enzyme, UFL1. Our data suggest that UFC1 lacks a key loop that is present in other E2 enzymes, and so functions in a novel mechanism. I will also provide structural data on the binding of UFC1 to UFL1. In addition, our work reveals the defects in ufmylation due to mutations in UFC1 that lead to severe early-onset encephalopathy, thereby providing a potential basis for drug design.