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Cell. 2016 Jun 2;165(6):1440-1453. doi: 10.1016/j.cell.2016.05.037.

Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C.

Author information

1
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Memphis, TN 38105, USA.
3
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), 1030 Vienna, Austria.
4
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
5
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S3E1, Canada.
6
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
7
Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA.
8
Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
9
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), 1030 Vienna, Austria. Electronic address: jan-michael.peters@imp.ac.at.
10
Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany. Electronic address: hstark1@gwdg.de.
11
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Memphis, TN 38105, USA. Electronic address: brenda.schulman@stjude.org.

Abstract

Protein ubiquitination involves E1, E2, and E3 trienzyme cascades. E2 and RING E3 enzymes often collaborate to first prime a substrate with a single ubiquitin (UB) and then achieve different forms of polyubiquitination: multiubiquitination of several sites and elongation of linkage-specific UB chains. Here, cryo-EM and biochemistry show that the human E3 anaphase-promoting complex/cyclosome (APC/C) and its two partner E2s, UBE2C (aka UBCH10) and UBE2S, adopt specialized catalytic architectures for these two distinct forms of polyubiquitination. The APC/C RING constrains UBE2C proximal to a substrate and simultaneously binds a substrate-linked UB to drive processive multiubiquitination. Alternatively, during UB chain elongation, the RING does not bind UBE2S but rather lures an evolving substrate-linked UB to UBE2S positioned through a cullin interaction to generate a Lys11-linked chain. Our findings define mechanisms of APC/C regulation, and establish principles by which specialized E3-E2-substrate-UB architectures control different forms of polyubiquitination.

PMID:
27259151
PMCID:
PMC4991212
DOI:
10.1016/j.cell.2016.05.037
[Indexed for MEDLINE]
Free PMC Article

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