HECT domain interaction with ubiquitin binding sites on Tsg101-UEV controls HIV-1 egress, maturation, and infectivity.
HECT
NMR
Nedd4
Tsg101
UEV
endocytic sorting
ubiquitin
viral budding
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
13
12
2022
revised:
05
01
2023
accepted:
06
01
2023
pubmed:
16
1
2023
medline:
25
2
2023
entrez:
15
1
2023
Statut:
ppublish
Résumé
The HECT domain of HECT E3 ligases consists of flexibly linked N- and C-terminal lobes, with a ubiquitin (Ub) donor site on the C-lobe that is directly involved in substrate modification. HECT ligases also possess a secondary Ub binding site in the N-lobe, which is thought to play a role in processivity, specificity, or regulation. Here, we report the use of paramagnetic solution NMR to characterize a complex formed between the isolated HECT domain of neural precursor cell-expressed developmentally downregulated 4-1 and the ubiquitin E2 variant (UEV) domain of tumor susceptibility gene 101 (Tsg101). Both proteins are involved in endosomal trafficking, a process driven by Ub signaling, and are hijacked by viral pathogens for particle assembly; however, a direct interaction between them has not been described, and the mechanism by which the HECT E3 ligase contributes to pathogen formation has not been elucidated. We provide evidence for their association, consisting of multiple sites on the neural precursor cell-expressed developmentally downregulated 4-1 HECT domain and elements of the Tsg101 UEV domain involved in noncovalent ubiquitin binding. Furthermore, we show using an established reporter assay that HECT residues perturbed by UEV proximity define determinants of viral maturation and infectivity. These results suggest the UEV interaction is a determinant of HECT activity in Ub signaling. As the endosomal trafficking pathway is hijacked by several human pathogens for egress, the HECT-UEV interaction could represent a potential novel target for therapeutic intervention.
Identifiants
pubmed: 36642186
pii: S0021-9258(23)00033-9
doi: 10.1016/j.jbc.2023.102901
pmc: PMC9944984
pii:
doi:
Substances chimiques
Endosomal Sorting Complexes Required for Transport
0
Tsg101 protein
0
Ubiquitin
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
102901Subventions
Organisme : NIAID NIH HHS
ID : R01 AI150489
Pays : United States
Organisme : NIMHD NIH HHS
ID : U54 MD007602
Pays : United States
Informations de copyright
Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
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