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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{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.

Authors:
; ; ; ; ; ; ; ;  [1];  [2];  [2];  [2]
  1. (BWH)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1050090
Resource Type:
Journal Article
Journal Name:
Mol. Cell
Additional Journal Information:
Journal Volume: 47; Journal Issue: (3) ; 08, 2012
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CHAINS; CRYSTAL STRUCTURE; DISEASES; LIGASES; MUTATIONS; PROTEINS

Citation Formats

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., LBNL), SJCH), and DFCI). Structure of a Glomulin-RBX1-CUL1 Complex: Inhibition of a RING E3 Ligase through Masking of Its E2-Binding Surface. United States: N. p., 2012. Web. doi:10.1016/j.molcel.2012.05.044.
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., LBNL), SJCH), & DFCI). Structure of a Glomulin-RBX1-CUL1 Complex: Inhibition of a RING E3 Ligase through Masking of Its E2-Binding Surface. United States. doi:10.1016/j.molcel.2012.05.044.
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., LBNL), SJCH), and DFCI). Thu . "Structure of a Glomulin-RBX1-CUL1 Complex: Inhibition of a RING E3 Ligase through Masking of Its E2-Binding Surface". United States. doi:10.1016/j.molcel.2012.05.044.
@article{osti_1050090,
title = {Structure of a Glomulin-RBX1-CUL1 Complex: Inhibition of a RING E3 Ligase through Masking of Its E2-Binding Surface},
author = {Duda, David M. and Olszewski, Jennifer L. and Tron, Adriana E. and Hammel, Michal and Lambert, Lester J. and Waddell, M. Brett and Mittag, Tanja and DeCaprio, James A. and Schulman, Brenda A. and LBNL) and SJCH) and DFCI)},
abstractNote = {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.},
doi = {10.1016/j.molcel.2012.05.044},
journal = {Mol. Cell},
number = (3) ; 08, 2012,
volume = 47,
place = {United States},
year = {2012},
month = {11}
}