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Structure of a glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface.

Molecular cell | Aug 10, 2012

The approximately 300 human cullin-RING ligases (CRLs) are multisubunit E3s in which a RING protein, either RBX1 or RBX2, recruits an E2 to catalyze ubiquitination. RBX1-containing CRLs also can bind Glomulin (GLMN), which binds RBX1's RING domain, regulates the RBX1-CUL1-containing SCF(FBW7) complex, and is disrupted in the disease Glomuvenous Malformation. Here we report the crystal structure of a complex between GLMN, RBX1, and a fragment of CUL1. Structural and biochemical analyses reveal that GLMN adopts a HEAT-like repeat fold that tightly binds the E2-interacting surface of RBX1, inhibiting CRL-mediated chain formation by the E2 CDC34. The structure explains the basis for GLMN's selectivity toward RBX1 over RBX2, and how disease-associated mutations disrupt GLMN-RBX1 interactions. Our study reveals a mechanism for RING E3 ligase regulation, whereby an inhibitor blocks E2 access, and raises the possibility that other E3s are likewise controlled by cellular proteins that mask E2-binding surfaces to mediate inhibition.

Pubmed ID: 22748924 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Anaphase-Promoting Complex-Cyclosome | Binding Sites | Carrier Proteins | Crystallography, X-Ray | Cullin Proteins | Glomus Tumor | Humans | Models, Chemical | Mutagenesis | Paraganglioma, Extra-Adrenal | Protein Binding | Protein Folding | Protein Structure, Tertiary | Structure-Activity Relationship | Substrate Specificity | Ubiquitin-Conjugating Enzymes | Ubiquitin-Protein Ligase Complexes | Ubiquitin-Protein Ligases | Ubiquitination

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Associated grants

  • Agency: NCI NIH HHS, Id: 5P30CA021765
  • Agency: NCI NIH HHS, Id: P01CA050661
  • Agency: NCRR NIH HHS, Id: P41 RR015301
  • Agency: NCI NIH HHS, Id: R01CA63113
  • Agency: NCRR NIH HHS, Id: RR-15301
  • Agency: NIGMS NIH HHS, Id: R01 GM069530
  • Agency: Howard Hughes Medical Institute, Id: P30 CA021765
  • Agency: NCI NIH HHS, Id: R01CA93804
  • Agency: NCI NIH HHS, Id: R01 CA093804
  • Agency: NCI NIH HHS, Id: R01GM069530
  • Agency: NIGMS NIH HHS, Id: P01 CA050661
  • Agency: NCI NIH HHS, Id: R01 CA063113
  • Agency: NCI NIH HHS, Id:

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