Molecular architecture of the ankyrin SOCS box family of Cul5-dependent E3 ubiquitin ligases

J Mol Biol. 2013 Sep 9;425(17):3166-77. doi: 10.1016/j.jmb.2013.06.015. Epub 2013 Jun 25.


Multi-subunit Cullin-RING E3 ligases often use repeat domain proteins as substrate-specific adaptors. Structures of these macromolecular assemblies are determined for the F-box-containing leucine-rich repeat and WD40 repeat families, but not for the suppressor of cytokine signaling (SOCS)-box-containing ankyrin repeat proteins (ASB1-18), which assemble with Elongins B and C and Cul5. We determined the crystal structures of the ternary complex of ASB9-Elongin B/C as well as the interacting N-terminal domain of Cul5 and used structural comparisons to establish a model for the complete Cul5-based E3 ligase. The structures reveal a distinct architecture of the ASB9 complex that positions the ankyrin domain coaxial to the SOCS box-Elongin B/C complex and perpendicular to other repeat protein complexes. This alternative architecture appears favorable to present the ankyrin domain substrate-binding site to the E2-ubiquitin, while also providing spacing suitable for bulky ASB9 substrates, such as the creatine kinases. The presented Cul5 structure also differs from previous models and deviates from other Cullins via a rigid-body rotation between Cullin repeats. This work highlights the adaptability of repeat domain proteins as scaffolds in substrate recognition and lays the foundation for future structure-function studies of this important E3 family.

Keywords: ASB; C-terminal domain; CTD; N-terminal domain; NTD; PDB; Protein Data Bank; SCF; SOCS; Skp1–Cul1–F-box; ankyrin SOCS box; degradation; proteasome; protein–protein interaction; signaling; suppressor of cytokine signaling; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Ankyrins / chemistry*
  • Ankyrins / genetics
  • Ankyrins / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Cullin Proteins / chemistry*
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism
  • Humans
  • Mice
  • Molecular Sequence Data
  • Protein Binding
  • Sequence Alignment
  • Suppressor of Cytokine Signaling Proteins / chemistry*
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Ubiquitin-Protein Ligases / chemistry*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism


  • Ankyrins
  • Cullin Proteins
  • Suppressor of Cytokine Signaling Proteins
  • Ubiquitin-Protein Ligases

Associated data

  • PDB/2WZK
  • PDB/3ZKJ