Molecular Architecture of the Ankyrin SOCS Box Family of Cul5-Dependent E3 Ubiquitin Ligases

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• 作者：Jo?o R.C. Muniz ; Kunde Guo ; Nadia J. Kershaw ; Vikram Ayinampudi ; Frank von Delft ; Jeffrey J. Babon ; Alex N. Bullock
• 关键词：NTD ; N-terminal domain ; CTD ; C-terminal domain ; PDB ; Protein Data Bank ; SOCS ; suppressor of cytokine signaling ; SCF ; Skp1&ndash ; Cul1&ndash ; F-box ; ASB ; ankyrin SOCS box
• 刊名：Journal of Molecular Biology
• 出版年：2013
• 出版时间：9 September, 2013
• 年：2013
• 卷：425
• 期：17
• 页码：3166-3177
• 全文大小：2514 K

文摘

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.