Inhibition of eukaryotic translation initiation by the marine natural product pateamine A.
Translation initiation in eukaryotes is accomplished through the coordinated and orderly action of a large number of proteins, including the eIF4 initiation factors. Herein, we report that pateamine A (PatA), a potent antiproliferative and proapoptotic marine natural product, inhibits cap-dependent eukaryotic translation initiation. PatA bound to and enhanced the intrinsic enzymatic activities of eIF4A, yet it inhibited eIF4A-eIF4G association and promoted the formation of a stable ternary complex between eIF4A and eIF4B. These changes in eIF4A affinity for its partner proteins upon binding to PatA caused the stalling of initiation complexes on mRNA in vitro and induced stress granule formation in vivo. These results suggest that PatA will be a valuable molecular probe for future studies of eukaryotic translation initiation and may serve as a lead compound for the development of anticancer agents.
Low
Woon-Kai
WK
Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
Dang
Yongjun
Y
Schneider-Poetsch
Tilman
T
Shi
Zonggao
Z
Choi
Nam Song
NS
Merrick
William C
WC
Romo
Daniel
D
Liu
Jun O
JO
D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology*; D005057:Eukaryotic Cells / Q000187:drug effects* / Q000378:metabolism; D039601:Eukaryotic Initiation Factor-4A / Q000187:drug effects / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000187:drug effects / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D018942:Macrolides; D015394:Molecular Structure; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000502:physiology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
D004852:Epoxy Compounds; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D018942:Macrolides; D013844:Thiazoles; C031799:eIF-4B; C421324:pateamine A; D039601:Eukaryotic Initiation Factor-4A