Dynamic states of eIF6 and SDS variants modulate interactions with uL14 of the 60S ribosomal subunit.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
28 02 2023
28 02 2023
Historique:
accepted:
22
12
2022
revised:
20
12
2022
received:
11
11
2022
pubmed:
19
1
2023
medline:
4
3
2023
entrez:
18
1
2023
Statut:
ppublish
Résumé
Assembly of ribosomal subunits into active ribosomal complexes is integral to protein synthesis. Release of eIF6 from the 60S ribosomal subunit primes 60S to associate with the 40S subunit and engage in translation. The dynamics of eIF6 interaction with the uL14 (RPL23) interface of 60S and its perturbation by somatic mutations acquired in Shwachman-Diamond Syndrome (SDS) is yet to be clearly understood. Here, by using a modified strategy to obtain high yields of recombinant human eIF6 we have uncovered the critical interface entailing eight key residues in the C-tail of uL14 that is essential for physical interactions between 60S and eIF6. Disruption of the complementary binding interface by conformational changes in eIF6 disease variants provide a mechanism for weakened interactions of variants with the 60S. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) analyses uncovered dynamic configurational rearrangements in eIF6 induced by binding to uL14 and exposed an allosteric interface regulated by the C-tail of eIF6. Disrupting key residues in the eIF6-60S binding interface markedly limits proliferation of cancer cells, which highlights the significance of therapeutically targeting this interface. Establishing these key interfaces thus provide a therapeutic framework for targeting eIF6 in cancers and SDS.
Identifiants
pubmed: 36651285
pii: 6991046
doi: 10.1093/nar/gkac1266
pmc: PMC9976893
doi:
Substances chimiques
Ribosomal Proteins
0
EIF6 protein, human
0
Eukaryotic Initiation Factors
0
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
1803-1822Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM130746
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM143179
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM149320
Pays : United States
Organisme : NIGMS NIH HHS
ID : R15 GM126477
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM133967
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL150146
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM139977
Pays : United States
Organisme : NIGMS NIH HHS
ID : R00 GM119173
Pays : United States
Organisme : NIH HHS
ID : S10 OD030343
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
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