Structure of a Glomulin-RBX1-CUL1 Complex: Inhibition of a RING E3 Ligase through Masking of Its E2-Binding Surface

Journal Article · Thu Nov 01 04:00:00 EDT 2012 · Mol. Cell

DOI:https://doi.org/10.1016/j.molcel.2012.05.044· OSTI ID:1050090

Duda, David M; Olszewski, Jennifer L; Tron, Adriana E; Hammel, Michal; Lambert, Lester J; Waddell, M Brett; Mittag, Tanja; DeCaprio, James A; Schulman, Brenda A ^[1]

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1. BWH

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{sup 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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE Office of Science (SC)
• OSTI ID: 1050090
• Journal Information: Mol. Cell, Journal Name: Mol. Cell Journal Issue: (3) ; 08, 2012 Vol. 47
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
CHAINS
CRYSTAL STRUCTURE
DISEASES
LIGASES
MUTATIONS
PROTEINS