The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation

Cell. 2011 Nov 23;147(5):1024-39. doi: 10.1016/j.cell.2011.10.035.

Abstract

The DDB1-CUL4-RBX1 (CRL4) ubiquitin ligase family regulates a diverse set of cellular pathways through dedicated substrate receptors (DCAFs). The DCAF DDB2 detects UV-induced pyrimidine dimers in the genome and facilitates nucleotide excision repair. We provide the molecular basis for DDB2 receptor-mediated cyclobutane pyrimidine dimer recognition in chromatin. The structures of the fully assembled DDB1-DDB2-CUL4A/B-RBX1 (CRL4(DDB2)) ligases reveal that the mobility of the ligase arm creates a defined ubiquitination zone around the damage, which precludes direct ligase activation by DNA lesions. Instead, the COP9 signalosome (CSN) mediates the CRL4(DDB2) inhibition in a CSN5 independent, nonenzymatic, fashion. In turn, CSN inhibition is relieved upon DNA damage binding to the DDB2 module within CSN-CRL4(DDB2). The Cockayne syndrome A DCAF complex crystal structure shows that CRL4(DCAF(WD40)) ligases share common architectural features. Our data support a general mechanism of ligase activation, which is induced by CSN displacement from CRL4(DCAF) on substrate binding to the DCAF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Cullin Proteins / chemistry
  • DNA Damage
  • DNA-Binding Proteins / chemistry
  • Enzyme Activation
  • Humans
  • Models, Molecular
  • Ubiquitin-Protein Ligases / chemistry*
  • Ubiquitin-Protein Ligases / metabolism
  • Xeroderma Pigmentosum Group A Protein / chemistry

Substances

  • CUL4A protein, human
  • Cullin Proteins
  • DDB1 protein, human
  • DDB2 protein, human
  • DNA-Binding Proteins
  • Xeroderma Pigmentosum Group A Protein
  • Ubiquitin-Protein Ligases

Associated data

  • PDB/4A08
  • PDB/4A09
  • PDB/4A0A
  • PDB/4A0B
  • PDB/4A0C
  • PDB/4A0K
  • PDB/4A0L
  • PDB/4A11