Who with whom: functional coordination of E2 enzymes by RING E3 ligases during poly-ubiquitylation.
E2 conjugating enzyme
ER-associated protein degradation
RING E3 ligase
linchpin
ubiquitin
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
16 11 2020
16 11 2020
Historique:
received:
01
03
2020
revised:
31
08
2020
accepted:
10
09
2020
pubmed:
6
10
2020
medline:
15
4
2021
entrez:
5
10
2020
Statut:
ppublish
Résumé
Protein modification with poly-ubiquitin chains is a crucial process involved in a myriad of cellular pathways. Chain synthesis requires two steps: substrate modification with ubiquitin (priming) followed by repetitive ubiquitin-to-ubiquitin attachment (elongation). RING-type E3 ligases catalyze both reactions in collaboration with specific priming and elongating E2 enzymes. We provide kinetic insight into poly-ubiquitylation during protein quality control by showing that priming is the rate-determining step in protein degradation as directed by the yeast ERAD RING E3 ligases, Hrd1 and Doa10. Doa10 cooperates with the dedicated priming E2, Ubc6, while both E3s use Ubc7 for elongation. Here, we provide direct evidence that Hrd1 uses Ubc7 also for priming. We found that Ubc6 has an unusually high basal activity that does not require strong stimulation from an E3. Doa10 exploits this property to pair with Ubc6 over Ubc7 during priming. Our work not only illuminates the mechanisms of specific E2/E3 interplay in ERAD, but also offers a basis to understand how RING E3s may have properties that are tailored to pair with their preferred E2s.
Identifiants
pubmed: 33015833
doi: 10.15252/embj.2020104863
pmc: PMC7667886
doi:
Substances chimiques
Saccharomyces cerevisiae Proteins
0
Ubiquitin
0
Polyubiquitin
120904-94-1
Poly A
24937-83-5
UBC6 protein, S cerevisiae
EC 2.3.2.23
UBC7 protein, S cerevisiae
EC 2.3.2.23
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
HRD1 protein, S cerevisiae
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e104863Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM088055
Pays : United States
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : RI 2874/1-1
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : SFB 740/TP B05
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : SPP 1365
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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