title: Insights into Cullin-RING E3 ubiquitin ligase recruitment: structure of the VHL-EloBC-Cul2 complex.
abstract: The von Hippel-Lindau tumor suppressor protein (VHL) recruits a Cullin 2 (Cul2) E3 ubiquitin ligase to downregulate HIF-1α, an essential transcription factor for the hypoxia response. Mutations in VHL lead to VHL disease and renal cell carcinomas. Inhibition of this pathway to upregulate erythropoietin production is a promising new therapy to treat ischemia and chronic anemia. Here, we report the crystal structure of VHL bound to a Cul2 N-terminal domain, Elongin B, and Elongin C (EloC). Cul2 interacts with both the VHL BC box and cullin box and a novel EloC site. Comparison with other cullin E3 ligase structures shows that there is a conserved, yet flexible, cullin recognition module and that cullin selectivity is influenced by distinct electrostatic interactions. Our structure provides a structural basis for the study of the pathogenesis of VHL disease and rationale for the design of novel compounds that may modulate cullin-substrate receptor interactions.
authors: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA.
authors: Henry C
authors: HC
authors: Nguyen
authors: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA.
authors: Haitao
authors: H
authors: Yang
authors: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA.
authors: Jennifer L
authors: JL
authors: Fribourgh
authors: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA.
authors: Leslie S
authors: LS
authors: Wolfe
authors: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA. Electronic address: yong.xiong@yale.edu.
authors: Yong
authors: Y
authors: Xiong
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D000075065:Elongin; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D014157:Transcription Factors / Q000737:chemistry*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry*
chemical_list: C000616396:ELOB protein, human; C000616395:ELOC protein, human; D000075065:Elongin; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human