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Title: Structural basis for catalytic activation by the human ZNF451 SUMO E3 ligase

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. In this paper, 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. Finally, our results are consistent with ZNF451 functioning as a bona fide SUMO E3 ligase.
 [1] ;  [2] ;  [3]
  1. Sloan Kettering Inst., New York, NY (United States). Structural Biology Program
  2. Max Planck Inst. of Immunobiology and Epigenetics, Freiburg (Germany). Dept. of Epigenetics
  3. Sloan Kettering Inst., New York, NY (United States). Structural Biology Program. Howard Hughes Medical Inst.
Publication Date:
OSTI Identifier:
Grant/Contract Number:
AC02-06CH11357; P41RR012408; P41GM103473; P41 GM103403; S10 RR029205; GM065872; P30 CA008748; DFG-SPP1365 PI 917/2-1
Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 22; Journal Issue: 12; Journal ID: ISSN 1545-9993
Nature Publishing Group
Research Org:
Sloan Kettering Inst., New York, NY (United States); Max Planck Inst. of Immunobiology and Epigenetics, Freiburg (Germany)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH) (United States); Max Planck Society (Germany); German Research Foundation (DFG)
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biochemistry; Structural biology; X-ray crystallography