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NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly
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NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly
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Journal Article
NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly
2020
Overview
Eukaryotic cell biology depends on cullin–RING E3 ligase (CRL)-catalysed protein ubiquitylation
1
, which is tightly controlled by the modification of cullin with the ubiquitin-like protein NEDD8
2
–
6
. However, how CRLs catalyse ubiquitylation, and the basis of NEDD8 activation, remain unknown. Here we report the cryo-electron microscopy structure of a chemically trapped complex that represents the ubiquitylation intermediate, in which the neddylated CRL1
β-TRCP
promotes the transfer of ubiquitin from the E2 ubiquitin-conjugating enzyme UBE2D to its recruited substrate, phosphorylated IκBα. NEDD8 acts as a nexus that binds disparate cullin elements and the RING-activated ubiquitin-linked UBE2D. Local structural remodelling of NEDD8 and large-scale movements of CRL domains converge to juxtapose the substrate and the ubiquitylation active site. These findings explain how a distinctive ubiquitin-like protein alters the functions of its targets, and show how numerous NEDD8-dependent interprotein interactions and conformational changes synergistically configure a catalytic CRL architecture that is both robust, to enable rapid ubiquitylation of the substrate, and fragile, to enable the subsequent functions of cullin–RING proteins.
A cryo-electron microscopy structure provides insights into the activation of cullin–RING E3 ligases by NEDD8 and the consequent catalysis of ubiquitylation reactions.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 82/29
/ 82/80
/ 82/83
/ 96
/ 96/95
/ Analysis
/ Cullin
/ Enzymes
/ Humanities and Social Sciences
/ Humans
/ Ligases
/ NEDD8 Protein - ultrastructure
/ NF-KappaB Inhibitor alpha - chemistry
/ NF-KappaB Inhibitor alpha - metabolism
/ NF-KappaB Inhibitor alpha - ultrastructure
/ Proteins
/ Science
/ Ubiquitin-conjugating enzyme
/ Ubiquitin-Conjugating Enzymes - chemistry
/ Ubiquitin-Conjugating Enzymes - metabolism
/ Ubiquitin-Conjugating Enzymes - ultrastructure
/ Ubiquitin-Protein Ligases - chemistry
/ Ubiquitin-Protein Ligases - metabolism
