Structure and dynamics of the ASB9 CUL-RING E3 Ligase

Nat Commun. 2020 Jun 8;11(1):2866. doi: 10.1038/s41467-020-16499-9.


The Cullin 5 (CUL5) Ring E3 ligase uses adaptors Elongins B and C (ELOB/C) to bind different SOCS-box-containing substrate receptors, determining the substrate specificity of the ligase. The 18-member ankyrin and SOCS box (ASB) family is the largest substrate receptor family. Here we report cryo-EM data for the substrate, creatine kinase (CKB) bound to ASB9-ELOB/C, and for full-length CUL5 bound to the RING protein, RBX2, which binds various E2s. To date, no full structures are available either for a substrate-bound ASB nor for CUL5. Hydrogen-deuterium exchange (HDX-MS) mapped onto a full structural model of the ligase revealed long-range allostery extending from the substrate through CUL5. We propose a revised allosteric mechanism for how CUL-E3 ligases function. ASB9 and CUL5 behave as rigid rods, connected through a hinge provided by ELOB/C transmitting long-range allosteric crosstalk from the substrate through CUL5 to the RBX2 flexible linker.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Creatine Kinase / metabolism*
  • Creatine Kinase / ultrastructure
  • Cryoelectron Microscopy*
  • Cullin Proteins / chemistry
  • Cullin Proteins / metabolism
  • Elongin / metabolism*
  • Elongin / ultrastructure
  • Humans
  • Models, Molecular
  • Protein Binding
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity
  • Suppressor of Cytokine Signaling Proteins / chemistry*
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • Suppressor of Cytokine Signaling Proteins / ultrastructure
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism


  • ASB9 protein, human
  • CUL5 protein, human
  • Cullin Proteins
  • Elongin
  • Protein Subunits
  • Suppressor of Cytokine Signaling Proteins
  • RNF7 protein, human
  • Ubiquitin-Protein Ligases
  • Creatine Kinase