8C06

Structure of Dimeric HECT E3 Ubiquitin Ligase UBR5

Summary for 8C06

• Entry DOI: 10.2210/pdb8c06/pdb
• EMDB information: 16355 16356 16865 16866 16867
• Descriptor: E3 ubiquitin-protein ligase UBR5, ZINC ION (2 entities in total)
• Functional Keywords: e3 ligase, ubr5, ubiquitination, ubq, ubiquitin, hect, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 1861989.58

Authors

Hehl, L.A.,Prabu, J.R.,Schulman, B.A. (deposition date: 2022-12-16, release date: 2023-08-23, Last modification date: 2024-02-14)

Primary citation

Hehl, L.A.,Horn-Ghetko, D.,Prabu, J.R.,Vollrath, R.,Vu, D.T.,Perez Berrocal, D.A.,Mulder, M.P.C.,van der Heden van Noort, G.J.,Schulman, B.A.
Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5.
Nat.Chem.Biol., 20:190-200, 2024

PubMed Abstract: Ubiquitin (Ub) chain formation by homologous to E6AP C-terminus (HECT)-family E3 ligases regulates vast biology, yet the structural mechanisms remain unknown. We used chemistry and cryo-electron microscopy (cryo-EM) to visualize stable mimics of the intermediates along K48-linked Ub chain formation by the human E3, UBR5. The structural data reveal a ≈ 620 kDa UBR5 dimer as the functional unit, comprising a scaffold with flexibly tethered Ub-associated (UBA) domains, and elaborately arranged HECT domains. Chains are forged by a UBA domain capturing an acceptor Ub, with its K48 lured into the active site by numerous interactions between the acceptor Ub, manifold UBR5 elements and the donor Ub. The cryo-EM reconstructions allow defining conserved HECT domain conformations catalyzing Ub transfer from E2 to E3 and from E3. Our data show how a full-length E3, ubiquitins to be adjoined, E2 and intermediary products guide a feed-forward HECT domain conformational cycle establishing a highly efficient, broadly targeting, K48-linked Ub chain forging machine.

PubMed: 37620400
DOI: 10.1038/s41589-023-01414-2

Experimental method

ELECTRON MICROSCOPY (2.7 Å)