HUWE1 employs a giant substrate-binding ring to feed and regulate its HECT E3 domain.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
14
02
2021
accepted:
08
06
2021
pubmed:
24
7
2021
medline:
13
10
2021
entrez:
23
7
2021
Statut:
ppublish
Résumé
HUWE1 is a universal quality-control E3 ligase that marks diverse client proteins for proteasomal degradation. Although the giant HECT enzyme is an essential component of the ubiquitin-proteasome system closely linked with severe human diseases, its molecular mechanism is little understood. Here, we present the crystal structure of Nematocida HUWE1, revealing how a single E3 enzyme has specificity for a multitude of unrelated substrates. The protein adopts a remarkable snake-like structure, where the C-terminal HECT domain heads an extended alpha-solenoid body that coils in on itself and houses various protein-protein interaction modules. Our integrative structural analysis shows that this ring structure is highly dynamic, enabling the flexible HECT domain to reach protein targets presented by the various acceptor sites. Together, our data demonstrate how HUWE1 is regulated by its unique structure, adapting a promiscuous E3 ligase to selectively target unassembled orphan proteins.
Identifiants
pubmed: 34294896
doi: 10.1038/s41589-021-00831-5
pii: 10.1038/s41589-021-00831-5
pmc: PMC7611724
mid: EMS127426
doi:
Substances chimiques
Caenorhabditis elegans Proteins
0
Fungal Proteins
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1084-1092Subventions
Organisme : European Research Council
ID : 694978
Pays : International
Organisme : Austrian Science Fund FWF
ID : F 7905
Pays : Austria
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
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