RNA-mediated sequestration of the RNA helicase eIF4A by Pateamine A inhibits translation initiation.
Eukaryotic initiation factor 4A (eIF4A) is a member of the DEAD-box family of putative RNA helicases whose members are involved in many aspects of RNA metabolism. eIF4A is thought to facilitate binding of 43S preinitiation complexes to mRNAs by unwinding secondary structures present in the 5' untranslated region. Pateamine A, a small-molecule inhibitor of translation initiation, acts in an unusual manner by stimulating eIF4A activity. Herein, we report the elucidation of pateamine's mode of action. We demonstrate that Pateamine A is a chemical inducer of dimerization that forces an engagement between eIF4A and RNA and prevents eIF4A from participating in the ribosome-recruitment step of translation initiation.
Bordeleau
Marie-Eve
ME
Department of Biochemistry, McGill University, McIntyre Medical Sciences Building, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada.
Cencic
Regina
R
Lindqvist
Lisa
L
Oberer
Monika
M
Northcote
Peter
P
Wagner
Gerhard
G
Pelletier
Jerry
J
D019281:Dimerization; D004852:Epoxy Compounds / Q000494:pharmacology*; D039601:Eukaryotic Initiation Factor-4A / Q000187:drug effects* / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D018942:Macrolides / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology*; D012313:RNA / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*
D004852:Epoxy Compounds; D039603:Eukaryotic Initiation Factor-4G; D018942:Macrolides; D046912:Multiprotein Complexes; D013844:Thiazoles; C421324:pateamine A; D012313:RNA; D039601:Eukaryotic Initiation Factor-4A