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PreprintCited by 8Ubiquitin and proteasome pathwaysEnzyme Structure and FunctionProtein Structure and Dynamics

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Structural ubiquitin contributes to K48 linkage-specificity of the HECT ligase Tom1

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Warner, Katrina, Hunkeler, Moritz, Baek, Kheewoong, Schmoker, Anna, Roy Burman, Shourya S., Overwijn, Daan, Jin, Cyrus, Donovan, Katherine A., Fischer, Eric S.·2024·Cell Reports
DOI 10.1101/2024.11.25.625210

Preprint — published as 10.1016/j.celrep.2025.115688

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Abstract

Summary: 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 encoded in the S. cerevisiae genome and 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 cryogenic electron microscopy (cryo-EM) of Tom1 during an active ubiquitylation cycle, we demonstrate that the extended domain architecture directly contributes to activity. We identify a Tom1–ubiquitin architecture during ubiquitylation 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.

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Metadata

Authors
Warner, K., Hunkeler, M., Baek, K., Schmoker, A., Roy Burman, S. S., Overwijn, D., Jin, C., Donovan, K. A., & Fischer, E. S.
Affiliations
  • Harvard University (US)
  • Dana-Farber Cancer Institute (US)
Corresponding author
Fischer, Eric S.
ORCID
Venue
Cell Reports
Publisher
openRxiv
Published
2024-11-25
Volume
44
Issue
5
Pages
115688-115688
ISSN
2211-1247 (ISSN-L)
DOI
10.1101/2024.11.25.625210
OpenAlex
W4410299632
Cited by
8
References
1
Citations by year
2026: 7 · 2025: 1
FWCI
2.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Damon Runyon Cancer Research Foundation (DRG-2514-24)
  • G. Harold and Leila Y. Mathers Charitable Foundation (-2103-01437)
  • Astellas Pharma US
  • G. Harold and Leila Y. Mathers Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
TOM1, HECT E3 ubiquitin ligase, ubiquitin binding site, ubiquitination, HUWE1, yeast, protein quality control, DNA damage response
MeSH terms
Binding Sites, Models, Molecular, Protein Binding, Saccharomyces cerevisiae, Cryoelectron Microscopy, Ubiquitin, Saccharomyces cerevisiae Proteins, Ubiquitin-Protein Ligases, Ubiquitination

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