8PQL

K48-linked ubiquitin chain formation with a cullin-RING E3 ligase and Cdc34: NEDD8-CUL2-RBX1-ELOB/C-FEM1C with trapped UBE2R2-donor UB-acceptor UB-SIL1 peptide

Summary for 8PQL

• Entry DOI: 10.2210/pdb8pql/pdb
• EMDB information: 17798 17799 17800 17801 17802 17803 17822
• Descriptor: Ubiquitin-conjugating enzyme E2 R2, ZINC ION, Polyubiquitin-C,Nucleotide exchange factor SIL1, ... (10 entities in total)
• Functional Keywords: cul2, fem1c, elobc, sil1, ubiquitin, ubiquitin ligase, ubiquitin chain formation, poliubiquitylation, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 377624.55

Authors

Liwocha, J.,Prabu, J.R.,Kleiger, G.,Schulman, B.A. (deposition date: 2023-07-11, release date: 2024-02-14, Last modification date: 2024-11-13)

Primary citation

Liwocha, J.,Li, J.,Purser, N.,Rattanasopa, C.,Maiwald, S.,Krist, D.T.,Scott, D.C.,Steigenberger, B.,Prabu, J.R.,Schulman, B.A.,Kleiger, G.
Mechanism of millisecond Lys48-linked poly-ubiquitin chain formation by cullin-RING ligases.
Nat.Struct.Mol.Biol., 31:378-389, 2024

PubMed Abstract: E3 ubiquitin ligases, in collaboration with E2 ubiquitin-conjugating enzymes, modify proteins with poly-ubiquitin chains. Cullin-RING ligase (CRL) E3s use Cdc34/UBE2R-family E2s to build Lys48-linked poly-ubiquitin chains to control an enormous swath of eukaryotic biology. Yet the molecular mechanisms underlying this exceptional linkage specificity and millisecond kinetics of poly-ubiquitylation remain unclear. Here we obtain cryogenic-electron microscopy (cryo-EM) structures that provide pertinent insight into how such poly-ubiquitin chains are forged. The CRL RING domain not only activates the E2-bound ubiquitin but also shapes the conformation of a distinctive UBE2R2 loop, positioning both the ubiquitin to be transferred and the substrate-linked acceptor ubiquitin within the active site. The structures also reveal how the ubiquitin-like protein NEDD8 uniquely activates CRLs during chain formation. NEDD8 releases the RING domain from the CRL, but unlike previous CRL-E2 structures, does not contact UBE2R2. These findings suggest how poly-ubiquitylation may be accomplished by many E2s and E3s.

PubMed: 38326650
DOI: 10.1038/s41594-023-01206-1

Experimental method

ELECTRON MICROSCOPY (3.76 Å)