Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5.

Autor: Hehl LA; Department of Chemistry, School of Natural Sciences, Technical University of Munich, Garching, Germany.; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany., Horn-Ghetko D; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany., Prabu JR; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany., Vollrath R; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany., Vu DT; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany., Pérez Berrocal DA; Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, the Netherlands., Mulder MPC; Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, the Netherlands., van der Heden van Noort GJ; Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, the Netherlands., Schulman BA; Department of Chemistry, School of Natural Sciences, Technical University of Munich, Garching, Germany. schulman@biochem.mpg.de.; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany. schulman@biochem.mpg.de.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2024 Feb; Vol. 20 (2), pp. 190-200. Date of Electronic Publication: 2023 Aug 24.
DOI: 10.1038/s41589-023-01414-2
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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