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NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly.


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 NEDD82-6. 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?-TRCP promotes the transfer of ubiquitin from the E2 ubiquitin-conjugating enzyme UBE2D to its recruited substrate, phosphorylated I?B?. 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.

SUBMITTER: Baek K 

PROVIDER: S-EPMC7050210 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly.

Baek Kheewoong K   Krist David T DT   Prabu J Rajan JR   Hill Spencer S   Klügel Maren M   Neumaier Lisa-Marie LM   von Gronau Susanne S   Kleiger Gary G   Schulman Brenda A BA  

Nature 20200212 7795


Eukaryotic cell biology depends on cullin-RING E3 ligase (CRL)-catalysed protein ubiquitylation<sup>1</sup>, which is tightly controlled by the modification of cullin with the ubiquitin-like protein NEDD8<sup>2-6</sup>. 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<sup>β-TRCP</sup> promo  ...[more]

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