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PDBsum entry 4f52
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Cell cycle/ligase/signaling protein
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PDB id
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4f52
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Contents |
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258 a.a.
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84 a.a.
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85 a.a.
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523 a.a.
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References listed in PDB file
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Key reference
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Title
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Structure of a glomulin-Rbx1-Cul1 complex: inhibition of a ring e3 ligase through masking of its e2-Binding surface.
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Authors
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D.M.Duda,
J.L.Olszewski,
A.E.Tron,
M.Hammel,
L.J.Lambert,
M.B.Waddell,
T.Mittag,
J.A.Decaprio,
B.A.Schulman.
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Ref.
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Mol Cell, 2012,
47,
371-382.
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PubMed id
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Abstract
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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 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.
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