Intermolecular β-sheet formation guides the interaction between ubiquitin-like modifier FAT10 and adapter protein NUB1L

Under inflammatory conditions, the ubiquitin-like modifier FAT10 targets proteins for rapid and irreversible degradation by the 26S proteasome. FAT10 is degraded along with its substrates; in this process, the weak folding of FAT10 and the adapter protein NUB1L are believed to play crucial roles. We report the investigation of the N-domain of FAT10 and its interaction with NUB1L by magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy. A stretch of residues that is unobserved when the N-domain of FAT10 is in its ubiquitin-like β-grasp fold, becomes part of an intermolecular β-sheet upon binding to NUB1L. The rest of the N-domain is stabilized in a disordered state, with exception of a series of anchor residues and the N-terminus. MAS NMR is thus able to experimentally capture, at the atomic level, the shapeshifting of FAT10. Binding of the N-terminus likely plays a critical role in the presentation of the unfolded N-domain to the proteasome.