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| Title | Structural ubiquitin contributes to K48 linkage specificity of the HECT ligase Tom1. |
|---|---|
| Journal, issue, pages | Cell Rep, Vol. 44, Issue 5, Page 115688, Year 2025 |
| Publish date | May 12, 2025 |
 Authors | Katrina Warner / Moritz Hunkeler / Kheewoong Baek / Anna Schmoker / Shourya S Roy Burman / Daan Overwijn / Cyrus Jin / Katherine A Donovan / Eric S Fischer /  |
| PubMed Abstract | Homologous to E6AP C terminus (HECT) ubiquitin ligases play key roles in essential pathways such as DNA repair, cell cycle control, or protein quality control. Tom1 is one of five HECT ubiquitin E3 ...Homologous to E6AP C terminus (HECT) ubiquitin ligases play key roles in essential pathways such as DNA repair, cell cycle control, or protein quality control. Tom1 is one of five HECT ubiquitin E3 ligases in budding yeast S. cerevisiae and is prototypical for a ligase with pleiotropic functions such as ubiquitin chain amplification, orphan quality control, and DNA damage response. Structures of full-length HECT ligases, including the Tom1 ortholog HUWE1, have been reported, but how domains beyond the conserved catalytic module contribute to catalysis remains largely elusive. Here, through cryoelectron microscopy (cryo-EM) snapshots of Tom1 during an active ubiquitination cycle, we demonstrate that the extended domain architecture directly contributes to activity. We identify a Tom1-ubiquitin architecture during ubiquitination involving a non-canonical ubiquitin-binding site in the solenoid shape of Tom1. We demonstrate that this ubiquitin-binding site coordinates a structural ubiquitin contributing to the fidelity of K48 poly-ubiquitin chain assembly. |
 External links | Cell Rep / PubMed:40359109 |
| Methods | EM (single particle) |
| Resolution | 2.8 - 4.9 Å |
| Structure data |  EMDB-47035: Cryo-EM map of full-length Tom1 (S. cerevisiae), HECT focus map  EMDB-47045: Cryo-EM map of full-length Tom1 (S. cerevisiae), ARLD1-4 focus map  EMDB-47046: Focus map, Cryo-EM map of Tom1-UBE2D2-ubiquitin complex  EMDB-47047: Cryo-EM map of non-crosslinked Tom1, open conformation  EMDB-47048: Cryo-EM map of full length S. cerevisiae Tom1, closed-ring conformation  EMDB-47049: Tom1 ubiquitylation cascade, closed-ring conformation  EMDB-47050: Cryo-EM of Tom1 ubiquitylation, open conformation  EMDB-47051: Cryo-EM of Tom1 ubiquitylation, class 3  EMDB-47052: Cryo-EM map of Tom1 ubiquitylation, class 5  EMDB-47053: Cryo-EM map of Tom1 ubiquitylation, class 4  EMDB-47054: Cryo-EM map of Tom1 ubiquitylation, class 6  EMDB-47055: Cryo EM map of Tom1 ubiquitylation, class 2  EMDB-47056: Tom1 ubiquitylation, class 1 EMDB-47057, PDB-9dns: EMDB-47058, PDB-9dnt: |
| Source |
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 Keywords | transferase/ligase / transferase / ubiquitin / ubiquitylation / ligase / transferase-ligase complex / ubiquitylation complex |
saccharomyces cerevisiae (brewer's yeast)
homo sapiens (human)