title: Structure of a glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface.
abstract: 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.
authors: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis TN 38105, USA.
authors: David M
authors: DM
authors: Duda
authors: Jennifer L
authors: JL
authors: Olszewski
authors: Adriana E
authors: AE
authors: Tron
authors: Michal
authors: M
authors: Hammel
authors: Lester J
authors: LJ
authors: Lambert
authors: M Brett
authors: MB
authors: Waddell
authors: Tanja
authors: T
authors: Mittag
authors: James A
authors: JA
authors: DeCaprio
authors: Brenda A
authors: BA
authors: Schulman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism; D064173:Anaphase-Promoting Complex-Cyclosome; D001665:Binding Sites / Q000502:physiology; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D044842:Cullin Proteins / Q000737:chemistry* / Q000378:metabolism; D005918:Glomus Tumor / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D016296:Mutagenesis / Q000502:physiology; D010236:Paraganglioma, Extra-Adrenal / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000502:physiology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000502:physiology; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes / Q000737:chemistry / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C100318:Cullin 1; D044842:Cullin Proteins; C103024:GLMN protein, human; C479529:RBX1 protein, human; C577447:CDC34 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases