Human tumor suppressor protein Pdcd4 binds at the mRNA entry channel in the 40S small ribosomal subunit.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 Aug 2024
08 Aug 2024
Historique:
received:
28
12
2023
accepted:
17
07
2024
medline:
9
8
2024
pubmed:
9
8
2024
entrez:
8
8
2024
Statut:
epublish
Résumé
Translation is regulated mainly in the initiation step, and its dysregulation is implicated in many human diseases. Several proteins have been found to regulate translational initiation, including Pdcd4 (programmed cell death gene 4). Pdcd4 is a tumor suppressor protein that prevents cell growth, invasion, and metastasis. It is downregulated in most tumor cells, while global translation in the cell is upregulated. To understand the mechanisms underlying translational control by Pdcd4, we used single-particle cryo-electron microscopy to determine the structure of human Pdcd4 bound to 40S small ribosomal subunit, including Pdcd4-40S and Pdcd4-40S-eIF4A-eIF3-eIF1 complexes. The structures reveal the binding site of Pdcd4 at the mRNA entry site in the 40S, where the C-terminal domain (CTD) interacts with eIF4A at the mRNA entry site, while the N-terminal domain (NTD) is inserted into the mRNA channel and decoding site. The structures, together with quantitative binding and in vitro translation assays, shed light on the critical role of the NTD for the recruitment of Pdcd4 to the ribosomal complex and suggest a model whereby Pdcd4 blocks the eIF4F-independent role of eIF4A during recruitment and scanning of the 5' UTR of mRNA.
Identifiants
pubmed: 39117603
doi: 10.1038/s41467-024-50672-8
pii: 10.1038/s41467-024-50672-8
doi:
Substances chimiques
PDCD4 protein, human
0
RNA-Binding Proteins
0
Apoptosis Regulatory Proteins
0
RNA, Messenger
0
Eukaryotic Initiation Factor-4A
EC 2.7.7.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6633Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM092927
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM152137
Pays : United States
Informations de copyright
© 2024. The Author(s).
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