SUMO's Intrinsically Disordered N-Terminus is an Intramolecular Inhibitor of SUMO - SIM Interactions

Abstract

Small Ubiquitin-related modifiers of the SUMO family are known to regulate thousands of proteins in eukaryotic cells. How specificity is achieved in target selection, in SUMO paralogue choice and in SUMO-dependent interactions is poorly understood. Few SUMO enzymes are known, and most enzymes, substrates and downstream effectors share a short SUMO interaction motif (SIM) that mediates low affinity interaction with the core of SUMO proteins. A unique but unexplained feature of SUMO proteins is their intrinsically disordered N-terminus. Here we identify the SUMO N-terminus as an intramolecular inhibitor, discriminator and regulator of SUMO-SIM interactions. Mutational analyses and Molecular Dynamics simulations reveal that it inhibits SIM binding by fast and fuzzy interactions with SUMO‘s core. Intriguingly, the inhibitory potential differs significantly for different SUMO paralogues and can be regulated by acetylation and phosphorylation. Together, these findings reveal a unique mechanism that contributes to the specificity of SUMOylation and SUMO-dependent interactions.