Interplay between reversible phosphorylation and irreversible ADP-ribosylation of eukaryotic translation elongation factor 2.
Pseudomonas exotoxin targeted therapy
amino acid deprivation
apoptosis
diphthamide
diphtheria toxin
Journal
Biological chemistry
ISSN: 1437-4315
Titre abrégé: Biol Chem
Pays: Germany
ID NLM: 9700112
Informations de publication
Date de publication:
26 03 2019
26 03 2019
Historique:
received:
07
06
2018
accepted:
11
09
2018
pubmed:
16
9
2018
medline:
18
12
2019
entrez:
16
9
2018
Statut:
ppublish
Résumé
The functionality of eukaryotic translation elongation factor 2 (eEF2) is modulated by phosphorylation, eEF2 is simultaneously the molecular target of ADP-ribosylating toxins. We analyzed the interplay between phosphorylation and diphthamide-dependent ADP-ribosylation. Phosphorylation does not require diphthamide, eEF2 without it still becomes phosphorylated. ADP-ribosylation not only modifies the H715 diphthamide but also inhibits phosphorylation of S595 located in proximity to H715, and stimulates phosphorylation of T56. S595 can be phosphorylated by CDK2 and CDK1 which affects EEF2K-mediated T56-phosphorylation. Thus, ADP-ribosylation and S595-phosphorylation by kinases occur within the same vicinity and both trigger T56-phosphorylation. Diphthamide is surface-accessible permitting access to ADP-ribosylating enzymes, the adjacent S595 side chain extends into the interior. This orientation is incompatible with phosphorylation, neither allowing kinase access nor phosphate attachment. S595 phosphorylation must therefore be accompanied by structural alterations affecting the interface to ADP-ribosylating toxins. In agreement with that, replacement of S595 with Ala, Glu or Asp prevents ADP-ribosylation. Phosphorylation (starvation) as well as ADP-ribosylation (toxins) inhibit protein synthesis, both affect the S595/H715 region of eEF2, both trigger T57-phosphorylation eliciting similar transcriptional responses. Phosphorylation is short lived while ADP-ribosylation is stable. Thus, phosphorylation of the S595/H715 'modifier region' triggers transient interruption of translation while ADP-ribosylation arrests irreversibly.
Identifiants
pubmed: 30218597
doi: 10.1515/hsz-2018-0280
pii: hsz-2018-0280
pmc: PMC8268772
mid: NIHMS1706968
doi:
Substances chimiques
EEF2K protein, human
EC 2.7.1.17
Elongation Factor 2 Kinase
EC 2.7.11.20
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
501-512Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC010298
Pays : United States
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