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Title: Mechanism of Polyubiquitination by Human Anaphase-Promoting Complex: RING Repurposing for Ubiquitin Chain Assembly

Polyubiquitination by E2 and E3 enzymes is a predominant mechanism regulating protein function. Some RING E3s, including anaphase-promoting complex/cyclosome (APC), catalyze polyubiquitination by sequential reactions with two different E2s. An initiating E2 ligates ubiquitin to an E3-bound substrate. Another E2 grows a polyubiquitin chain on the ubiquitin-primed substrate through poorly defined mechanisms. Here in this paper we show that human APC’s RING domain is repurposed for dual functions in polyubiquitination. The canonical RING surface activates an initiating E2-ubiquitin intermediate for substrate modification. However, APC engages and activates its specialized ubiquitin chain-elongating E2 UBE2S in ways that differ from current paradigms. During chain assembly, a distinct APC11 RING surface helps deliver a substrate-linked ubiquitin to accept another ubiquitin from UBE2S. Our data define mechanisms of APC/UBE2S-mediated polyubiquitination, reveal diverse functions of RING E3s and E2s, and provide a framework for understanding distinctive RING E3 features specifying ubiquitin chain elongation.
Authors:
 [1] ;  [2] ;  [3] ;  [3] ;  [4] ;  [1] ;  [1] ;  [3] ;  [5] ;  [3] ;  [1] ;  [1] ;  [1] ;  [3] ;  [1] ;  [1] ;  [6] ;  [3] ;  [7] ;  [1]
  1. St. Jude Children's Research Hospital, Memphis, TN (United States). Dept. of Structural Biology
  2. St. Jude Children's Research Hospital, Memphis, TN (United States). Dept. of Structural Biology; Univ. of Tennessee Health Sciences Center, Memphis, TN (United States). Dept. of Microbiology, Immunology and Biochemistry
  3. Research Inst. of Molecular Pathology (IMP), Vienna (Austria)
  4. St. Jude Children's Research Hospital, Memphis, TN (United States). Dept. of Structural Biology; St. Jude Children's Research Hospital, Memphis, TN (United States). Howard Hughes Medical Inst.
  5. Max Planck Inst. for Biophysical Chemistry, Gottingen (Germany); Georg-August Univ., Gottingen (Germany). Dept. of 3D Electron Cryomicroscopy, Inst. of Microbiology and Genetics
  6. Cornell Univ., Argonne, IL (United States). Dept. of Chemistry and Chemical Biology
  7. Max Planck Inst. for Biophysical Chemistry, Gottingen (Germany); Georg-August Univ., Gottingen (Germany). Dept. of 3D Electron Cryomicroscopy, Inst. of Microbiology and Genetics
Publication Date:
OSTI Identifier:
1227558
Grant/Contract Number:
227764; AC02-06CH11357
Type:
Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Volume: 56; Journal Issue: 2; Journal ID: ISSN 1097-2765
Publisher:
Elsevier - Cell Press
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC); Jane Coffin Childs Foundation; German Research Foundation (DFG); Austrian Research Fund
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES