6FX4
Disulfide between E3 HECT ligase Smurf2 and Ubiquitin G76C
Summary for 6FX4
| Entry DOI | 10.2210/pdb6fx4/pdb |
| Descriptor | E3 ubiquitin-protein ligase SMURF2, Polyubiquitin-B, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | e3 hect ligase, ubiquitin transfer, ligase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 45319.67 |
| Authors | Jaeckl, M.,Holdermann, I.,Wiesner, S. (deposition date: 2018-03-08, release date: 2018-07-11, Last modification date: 2024-11-13) |
| Primary citation | Jackl, M.,Stollmaier, C.,Strohaker, T.,Hyz, K.,Maspero, E.,Polo, S.,Wiesner, S. beta-Sheet Augmentation Is a Conserved Mechanism of Priming HECT E3 Ligases for Ubiquitin Ligation. J. Mol. Biol., 430:3218-3233, 2018 Cited by PubMed Abstract: Ubiquitin (Ub) ligases (E3s) catalyze the attachment of Ub chains to target proteins and thereby regulate a wide array of signal transduction pathways in eukaryotes. In HECT-type E3s, Ub first forms a thioester intermediate with a strictly conserved Cys in the C-lobe of the HECT domain and is then ligated via an isopeptide bond to a Lys residue in the substrate or a preceding Ub in a poly-Ub chain. To date, many key aspects of HECT-mediated Ub transfer have remained elusive. Here, we provide structural and functional insights into the catalytic mechanism of the HECT-type ligase Huwe1 and compare it to the unrelated, K63-specific Smurf2 E3, a member of the Nedd4 family. We found that the Huwe1 HECT domain, in contrast to Nedd4-family E3s, prioritizes K6- and K48-poly-Ub chains and does not interact with Ub in a non-covalent manner. Despite these mechanistic differences, we demonstrate that the architecture of the C-lobe~Ub intermediate is conserved between Huwe1 and Smurf2 and involves a reorientation of the very C-terminal residues. Moreover, in Nedd4 E3s and Huwe1, the individual sequence composition of the Huwe1 C-terminal tail modulates ubiquitination activity, without affecting thioester formation. In sum, our data suggest that catalysis of HECT ligases hold common features, such as the β-sheet augmentation that primes the enzymes for ligation, and variable elements, such as the sequence of the HECT C-terminal tail, that fine-tune ubiquitination activity and may aid in determining Ub chain specificity by positioning the substrate or acceptor Ub. PubMed: 29964046DOI: 10.1016/j.jmb.2018.06.044 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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