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

被引:64
|
作者
Duda, David M. [1 ,2 ]
Olszewski, Jennifer L. [1 ]
Tron, Adriana E. [4 ,5 ,6 ]
Hammel, Michal [7 ]
Lambert, Lester J. [1 ]
Waddell, M. Brett [3 ]
Mittag, Tanja [1 ]
DeCaprio, James A. [4 ,5 ,6 ]
Schulman, Brenda A. [1 ,2 ]
机构
[1] St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
[2] St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USA
[3] St Jude Childrens Res Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA
[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA
[5] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[6] Harvard Univ, Sch Med, Boston, MA 02115 USA
[7] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA
关键词
MITOTIC CHECKPOINT COMPLEX; SCFCDC4 UBIQUITIN LIGASE; GLOMUVENOUS MALFORMATIONS; SUBSTRATE RECOGNITION; CONFORMATIONAL-CHANGE; ALLOSTERIC INHIBITOR; SCF; ACTIVATION; GLOMULIN; BINDING;
D O I
10.1016/j.molcel.2012.05.044
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:371 / 382
页数:12
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