2. Academic Validation
  3. Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C

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

  • Cell. 2016 Jun 2;165(6):1440-1453. doi: 10.1016/j.cell.2016.05.037.
Nicholas G Brown 1,  Ryan VanderLinden 2,  Edmond R Watson 1,  Florian Weissmann 3,  Alban Ordureau 4,  Kuen-Phon Wu 1,  Wei Zhang 5,  Shanshan Yu 1,  Peter Y Mercredi 1,  Joseph S Harrison 6,  Iain F Davidson 3,  Renping Qiao 3,  Ying Lu 7,  Prakash Dube 8,  Michael R Brunner 1,  Christy R R Grace 1,  Darcie J Miller 1,  David Haselbach 8,  Marc A Jarvis 3,  Masaya Yamaguchi 1,  David Yanishevski 1,  Georg Petzold 3,  Sachdev S Sidhu 5,  Brian Kuhlman 6,  Marc W Kirschner 7,  J Wade Harper 4,  Jan-Michael Peters 9,  Holger Stark 10,  Brenda A Schulman 11
Affiliations

Affiliations

  • 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: [email protected].
  • 10 Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany. Electronic address: [email protected].
  • 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: [email protected].
PMID: 27259151 DOI: 10.1016/j.cell.2016.05.037
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.

Figures