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Molecular cell, 2012-08, Vol.47 (3), p.371-382
2012
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Details
- Autor(en) / Beteiligte
- Titel
- Structure of a Glomulin-RBX1-CUL1 Complex: Inhibition of a RING E3 Ligase through Masking of Its E2-Binding Surface
- Ist Teil von
- Molecular cell, 2012-08, Vol.47 (3), p.371-382
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 SCFFBW7 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. [Display omitted] ► Glomulin (GLMN) binds with about 40 nM Kd to RBX1 but not other related RING E3s ► A crystal structure shows GLMN binding RBX1's E2-interacting surface ► Biochemical and NMR data indicate GLMN inhibits RBX1 E3 by blocking E2 access ► The structure suggests GVM disease mutations would prevent GLMN binding to RBX1
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1097-2765eISSN: 1097-4164DOI: 10.1016/j.molcel.2012.05.044Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3477590
- Format
- –
- Schlagworte
- abnormal development, Adaptor Proteins, Signal Transducing - chemistry, Adaptor Proteins, Signal Transducing - metabolism, Anaphase-Promoting Complex-Cyclosome, Binding Sites - physiology, Carrier Proteins - chemistry, Carrier Proteins - metabolism, crystal structure, Crystallography, X-Ray, Cullin Proteins - chemistry, Cullin Proteins - metabolism, Glomus Tumor - metabolism, Humans, Models, Chemical, Mutagenesis - physiology, mutation, Paraganglioma, Extra-Adrenal - metabolism, Protein Binding - physiology, Protein Folding, Protein Structure, Tertiary - physiology, proteins, Structure-Activity Relationship, Substrate Specificity - physiology, Ubiquitin-Conjugating Enzymes, ubiquitin-protein ligase, Ubiquitin-Protein Ligase Complexes - chemistry, Ubiquitin-Protein Ligase Complexes - metabolism, Ubiquitin-Protein Ligases - antagonists & inhibitors, Ubiquitin-Protein Ligases - chemistry, Ubiquitin-Protein Ligases - metabolism, ubiquitination, Ubiquitination - physiology