Journal
MOLECULAR CELL
Volume 47, Issue 3, Pages 371-382Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2012.05.044
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Funding
- ALSAC
- PHS [5P30CA021765, R01GM069530, RO1CA93804, R01CA63113, P01CA050661]
- Pew Charitable Trust
- International Human Frontier Science Program
- NIH NCRR [RR-15301]
- US DOE [DE-AC02-05CH11231, W-31-109-ENG-38]
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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.
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