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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anaphase-Promoting Complex-Cyclosome / chemistry*
  • Anaphase-Promoting Complex-Cyclosome / metabolism*
  • Biocatalysis
  • Cryoelectron Microscopy
  • Humans
  • Models, Molecular
  • Saccharomyces cerevisiae Proteins / chemistry
  • Structure-Activity Relationship
  • Ubiquitin / metabolism*
  • Ubiquitin-Conjugating Enzymes / metabolism*
  • Ubiquitination


  • Saccharomyces cerevisiae Proteins
  • Ubiquitin
  • UBE2C protein, human
  • Ubiquitin-Conjugating Enzymes
  • Anaphase-Promoting Complex-Cyclosome