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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.

Original publication




Journal article


J Mol Biol

Publication Date





3166 - 3177


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