NEDD8 Nucleates a Multivalent Cullin–RING–UBE2D Ubiquitin Ligation Assembly
Document Type
Article
Publication Date
2-12-2020
Publication Title
Nature
Volume
578
First page number:
461
Last page number:
466
Abstract
Eukaryotic cell biology depends on cullin–RING E3 ligase (CRL)-catalysed protein ubiquitylation1, which is tightly controlled by the modification of cullin with the ubiquitin-like protein NEDD82,3,4,5,6. 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 CRL1β-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.
Disciplines
Cell and Developmental Biology | Cell Biology | Life Sciences
Language
English
Repository Citation
Baek, K.,
Krist, D. A.,
Prabu, J. R.,
Hill, S.,
Klügel, M.,
Neumaier, L.,
Gronau, S. V.,
Kleiger, G.,
Schulman, B. A.
(2020).
NEDD8 Nucleates a Multivalent Cullin–RING–UBE2D Ubiquitin Ligation Assembly.
Nature, 578
461-466.
http://dx.doi.org/10.1038/s41586-020-2000-y