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Structure. 2015 Mar 3;23(3):441-449. doi: 10.1016/j.str.2014.12.014. Epub 2015 Feb 5.

Insights into Cullin-RING E3 ubiquitin ligase recruitment: structure of the VHL-EloBC-Cul2 complex.

Author information

1
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA.
2
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA. Electronic address: yong.xiong@yale.edu.

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.

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PMID:
25661653
PMCID:
PMC4351159
DOI:
10.1016/j.str.2014.12.014
[Indexed for MEDLINE]
Free PMC Article

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