6TTU

Ubiquitin Ligation to substrate by a cullin-RING E3 ligase at 3.7A resolution: NEDD8-CUL1-RBX1 N98R-SKP1-monomeric b-TRCP1dD-IkBa-UB~UBE2D2

Summary for 6TTU

• Entry DOI: 10.2210/pdb6ttu/pdb
• EMDB information: 10578 10579 10580 10581 10582 10583 10585
• Descriptor: F-box/WD repeat-containing protein 1A, S-phase kinase-associated protein 1, Cullin-1, ... (9 entities in total)
• Functional Keywords: ubiquitin, e3 ligase, nedd8, cullin, cul1, rbx1, skp1, trcp, ube2d, ikbalpha, neddylation, ubiquitylation, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 227736.25

Authors

Baek, K.,Prabu, J.R.,Schulman, B.A. (deposition date: 2019-12-30, release date: 2020-02-12, Last modification date: 2024-10-23)

Primary citation

Baek, K.,Krist, D.T.,Prabu, J.R.,Hill, S.,Klugel, M.,Neumaier, L.M.,von Gronau, S.,Kleiger, G.,Schulman, B.A.
NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly.
Nature, 578:461-466, 2020

PubMed Abstract: Eukaryotic cell biology depends on cullin-RING E3 ligase (CRL)-catalysed protein ubiquitylation, which is tightly controlled by the modification of cullin with the ubiquitin-like protein NEDD8. 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 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.

PubMed: 32051583
DOI: 10.1038/s41586-020-2000-y

Experimental method

ELECTRON MICROSCOPY (3.7 Å)