Substrate-dependent targeting of eukaryotic translation initiation factor 4A by pateamine A: negation of domain-linker regulation of activity.
Central to cap-dependent eukaryotic translation initiation is the eIF4F complex, which is composed of the three eukaryotic initiation factors eIF4E, eIF4G, and eIF4A. eIF4A is an RNA-dependent ATPase and an ATP-dependent helicase that unwinds local secondary structure in mRNA to allow binding of the 43S ribosomal complex. The marine natural product pateamine A (PatA) has been demonstrated to inhibit cap-dependent initiation by targeting eIF4A and disrupting its protein-protein interactions while increasing its enzymatic activities. Here we demonstrate that the increased activity is caused by the induction of global conformational changes within eIF4A. Furthermore, binding of PatA is dependent on substrate (RNA and ATP) binding, and the increased activity upon PatA binding is caused by relief of a negative regulatory function of the eIF4A unique domain linker.
Low
Woon-Kai
WK
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Dang
Yongjun
Y
Bhat
Shridhar
S
Romo
Daniel
D
Liu
Jun O
JO
D000251:Adenosine Triphosphatases / Q000378:metabolism; D020134:Catalytic Domain; D004591:Electrophoresis, Polyacrylamide Gel; D004852:Epoxy Compounds / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D018942:Macrolides / Q000494:pharmacology*; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics; D011487:Protein Conformation; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D013379:Substrate Specificity; D013844:Thiazoles / Q000494:pharmacology*
D004852:Epoxy Compounds; D018942:Macrolides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013844:Thiazoles; C421324:pateamine A; D039601:Eukaryotic Initiation Factor-4A; D000251:Adenosine Triphosphatases