title: Ubc13: the Lys63 ubiquitin chain building machine.
abstract: Ubc13 is an ubiquitin E2 conjugating enzyme that participates with many different E3 ligases to form lysine 63-linked (Lys63) ubiquitin chains that are critical to signaling in inflammatory and DNA damage response pathways. Recent studies have suggested Ubc13 as a potential therapeutic target for intervention in various human diseases including several different cancers, alleviation of anti-cancer drug resistance, chronic inflammation, and viral infections. Understanding a potential therapeutic target from different angles is important to assess its usefulness and potential pitfalls. Here we present a global review of Ubc13 from its structure, function, and cellular activities, to its natural and chemical inhibition. The aim of this article is to review the literature that directly implicates Ubc13 in a biological function, and to integrate structural and mechanistic insights into the larger role of this critical E2 enzyme. We discuss observations of multiple Ubc13 structures that suggest a novel mechanism for activation of Ubc13 that involves conformational change of the active site loop.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Hodge
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Leo
authors.initials: L
authors.lastname: Spyracopoulos
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: J N Mark
authors.initials: JN
authors.lastname: Glover
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use; D004249:DNA Damage; D004260:DNA Repair; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D013329:Structure-Activity Relationship; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes
keywords: Mms2; RING E3 ligase; Ubc13; Uev1A; ubiquitination