Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex

Teresa A. F. Cardote, Morgan S. Gadd, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)
180 Downloads (Pure)

Abstract

Cullin RING E3 ubiquitin ligases (CRLs) function in the ubiquitin proteasome system to catalyze the transfer of ubiquitin from E2 conjugating enzymes to specific substrate proteins. CRLs are large dynamic complexes and attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. The atomic details of whole CRL assembly and interactions that dictate subunit specificity remain elusive. Here we present the crystal structure of a pentameric CRL2VHL complex, composed of Cul2, Rbx1, Elongin B, Elongin C and pVHL. The structure traps a closed state of full-length Cul2 and a new pose of Rbx1 in a trajectory from closed to open conformation. We characterize hotspots and binding thermodynamics at the interface between Cul2 and pVHL-EloBC and identify mutations that contribute toward a selectivity switch for Cul2 vs. Cul5 recognition. Our findings provide structural and biophysical insights into whole Cul2 complex that could aid future drug targeting.
Original languageEnglish
Pages (from-to)901-911.e3
Number of pages14
JournalStructure
Volume25
Issue number6
DOIs
Publication statusPublished - 6 Jun 2017

Keywords

  • Cullin-RING E3 ubiquitin ligases
  • Protein-protein interactions
  • VHL
  • Cullin-2
  • RING domain proteins

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