title: Structural basis for catalytic activation by the human ZNF451 SUMO E3 ligase.
abstract: E3 protein ligases enhance transfer of ubiquitin-like (Ubl) proteins from E2 conjugating enzymes to substrates by stabilizing the thioester-charged E2~Ubl in a closed configuration optimally aligned for nucleophilic attack. Here, we report biochemical and structural data that define the N-terminal domain of the Homo sapiens ZNF451 as the catalytic module for SUMO E3 ligase activity. The ZNF451 catalytic module contains tandem SUMO-interaction motifs (SIMs) bridged by a Pro-Leu-Arg-Pro (PLRP) motif. The first SIM and PLRP motif engage thioester-charged E2~SUMO while the next SIM binds a second molecule of SUMO bound to the back side of E2. We show that ZNF451 is SUMO2 specific and that SUMO modification of ZNF451 may contribute to activity by providing a second molecule of SUMO that interacts with E2. Our results are consistent with ZNF451 functioning as a bona fide SUMO E3 ligase.
authors.affiliation: Structural Biology Program, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Cappadocia
authors.affiliation: Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pichler
authors.affiliation: Structural Biology Program, Sloan Kettering Institute, New York, New York, USA.|Howard Hughes Medical Institute, Sloan Kettering Institute, New York, New York, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Lima
mesh_terms: D020816:Amino Acid Motifs; D019881:Aminoacyltransferases; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation; D025842:SUMO-1 Protein / Q000737:chemistry* / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D025842:SUMO-1 Protein; D014157:Transcription Factors; D019881:Aminoacyltransferases; C531551:ZNF451 protein, human; D044767:Ubiquitin-Protein Ligases