Cullin-independent recognition of HHARI substrates by a dynamic RBR catalytic domain.
4EHP
AriH1
HDX-MS
HHARI
RING-between-RING
XL-MS
mono-ubiquitination
ubiquitin
Journal
Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697
Informations de publication
Date de publication:
01 09 2022
01 09 2022
Historique:
received:
02
02
2022
revised:
15
04
2022
accepted:
24
05
2022
pubmed:
19
6
2022
medline:
9
9
2022
entrez:
18
6
2022
Statut:
ppublish
Résumé
RING-between-RING (RBR) E3 ligases mediate ubiquitin transfer through an obligate E3-ubiquitin thioester intermediate prior to substrate ubiquitination. Although RBRs share a conserved catalytic module, substrate recruitment mechanisms remain enigmatic, and the relevant domains have yet to be identified for any member of the class. Here we characterize the interaction between the auto-inhibited RBR, HHARI (AriH1), and its target protein, 4EHP, using a combination of XL-MS, HDX-MS, NMR, and biochemical studies. The results show that (1) a di-aromatic surface on the catalytic HHARI Rcat domain forms a binding platform for substrates and (2) a phosphomimetic mutation on the auto-inhibitory Ariadne domain of HHARI promotes release and reorientation of Rcat for transthiolation and substrate modification. The findings identify a direct binding interaction between a RING-between-RING ligase and its substrate and suggest a general model for RBR substrate recognition.
Identifiants
pubmed: 35716664
pii: S0969-2126(22)00224-6
doi: 10.1016/j.str.2022.05.017
pmc: PMC9444911
mid: NIHMS1812642
pii:
doi:
Substances chimiques
Cullin Proteins
0
Ubiquitin
0
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
1269-1284.e6Subventions
Organisme : NIGMS NIH HHS
ID : F32 GM120797
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI153191
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM088055
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM103533
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG066574
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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