title: SUMO-mimicking peptides inhibiting protein SUMOylation.
abstract: The ubiquitin-like protein SUMO is transferred through a core E1-E2 cascade composed of the SUMO-activating enzyme (SAE) and Ubc9 to modify cellular proteins and transmit important biological signals. SAE primarily recognizes the C-terminal tail of SUMO and catalyzes ATP condensation with the SUMO C-terminal carboxylate to activate its transfer through the cascade. Here, we used phage display to show that a broad profile of SUMO C-terminal sequences could be activated by SAE. Based on this, we developed heptamer peptides that could 1) form thioester conjugates with SAE, 2) be transferred from SAE to Ubc9, and 3) be further transferred to the SUMOylation target protein RanGAP1. As these peptides recapitulate the action of SUMO in protein modification, we refer to them as "SUMO-mimicking peptides". We found that, once the peptides were conjugated to SAE and Ubc9, they blocked full-length SUMO from entering the cascade. These peptides can thus function as mechanism-based inhibitors of the protein SUMOylation reaction.
authors.affiliation: Department of Chemistry, University of Chicago, Chicago, IL 60637 (USA).
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.forename: Eric B
authors.initials: EB
authors.lastname: Villhauer
authors.forename: Karan
authors.initials: K
authors.lastname: Bhuripanyo
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kiyokawa
authors.forename: Hermann
authors.initials: H
authors.lastname: Schindelin
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D008958:Models, Molecular; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D058207:Sumoylation / Q000187:drug effects*; D044764:Ubiquitin-Activating Enzymes / Q000737:chemistry / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D019151:Peptide Library; D010455:Peptides; D044763:Ubiquitin-Conjugating Enzymes; C470299:SAE1 protein, human; D044764:Ubiquitin-Activating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9
keywords: SUMO; SUMO activating enzyme; SUMOylation; peptide inhibitor; phage display