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

Publication Type:

Journal Article


Mol Cell, Volume 47, Issue 3, p.371-82 (2012)


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


<p>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.</p>