دورية
Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5
| العنوان: | Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5 |
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| المؤلفون: | Hehl, Laura A., Horn-Ghetko, Daniel, Prabu, J. Rajan, Vollrath, Ronnald, Vu, D. Tung, Pérez Berrocal, David A., Mulder, Monique P. C., van der Heden van Noort, Gerbrand J., Schulman, Brenda A. |
| المصدر: | Nature Chemical Biology; 20230101, Issue: Preprints p1-11, 11p |
| مستخلص: | 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. |
| قاعدة البيانات: | Supplemental Index |
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