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PDBsum entry 6r6h
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Contents |
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419 a.a.
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428 a.a.
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400 a.a.
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405 a.a.
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310 a.a.
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281 a.a.
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172 a.a.
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745 a.a.
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105 a.a.
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99 a.a.
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86 a.a.
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150 a.a.
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206 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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Structural basis of cullin 2 ring e3 ligase regulation by the cop9 signalosome.
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Authors
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S.V.Faull,
A.M.C.Lau,
C.Martens,
Z.Ahdash,
K.Hansen,
H.Yebenes,
C.Schmidt,
F.Beuron,
N.B.Cronin,
E.P.Morris,
A.Politis.
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Ref.
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Nat Commun, 2019,
10,
3814.
[DOI no: ]
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PubMed id
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Abstract
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Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through
specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by
removing NEDD8 from activated Cullins. Here we present structures of the
neddylated and deneddylated CSN-CRL2 complexes by combining single-particle
cryo-electron microscopy (cryo-EM) with chemical cross-linking mass spectrometry
(XL-MS). These structures suggest a conserved mechanism of CSN activation,
consisting of conformational clamping of the CRL2 substrate by CSN2/CSN4,
release of the catalytic CSN5/CSN6 heterodimer and finally activation of the
CSN5 deneddylation machinery. Using hydrogen-deuterium exchange (HDX)-MS we
show that CRL2 activates CSN5/CSN6 in a neddylation-independent manner. The
presence of NEDD8 is required to activate the CSN5 active site. Overall, by
synergising cryo-EM with MS, we identify sensory regions of the CSN that mediate
its stepwise activation and provide a framework for understanding the regulatory
mechanism of other Cullin family members.
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