SUMO’s intrinsically disordered N-terminus is an intramolecular inhibitor of SUMO - SIM interactions

Abstract

Small Ubiquitin-related modifiers of the SUMO family regulate thousands of proteins in eukaryotic cells. Many SUMO substrates, effectors and enzymes carry short motifs (SIMs) that mediate low affinity interactions with SUMO proteins. This raises the question how specificity is achieved in target selection, SUMO paralogue choice and SUMO-dependent interactions. A unique but poorly understood feature of SUMO proteins is their intrinsically disordered N-terminus. We reveal a function for N-termini of human, C. elegans, and yeast SUMO proteins as intramolecular inhibitors of SUMO-SIM interactions. Mutational analyses, NMR spectroscopy, and Molecular Dynamics simulations indicate that SUMO’s N-terminus can inhibit SIM binding by fast and fuzzy interactions with SUMO‘s core. Deletion of the C. elegans SUMO1 N-terminus leads to p53-dependent apoptosis during germline development, indicating an important role of SUMO’s N-termini in DNA damage repair. Our findings reveal a mechanism of disorder-based autoinhibition that contributes to the specificity of SUMOylation and SUMO-dependent interactions.