title: Substrate-dependent targeting of eukaryotic translation initiation factor 4A by pateamine A: negation of domain-linker regulation of activity.
abstract: 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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Woon-Kai
authors.initials: WK
authors.lastname: Low
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Dang
authors.forename: Shridhar
authors.initials: S
authors.lastname: Bhat
authors.forename: Daniel
authors.initials: D
authors.lastname: Romo
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
mesh_terms: 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*
chemical_list: D004852:Epoxy Compounds; D018942:Macrolides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013844:Thiazoles; C421324:pateamine A; D039601:Eukaryotic Initiation Factor-4A; D000251:Adenosine Triphosphatases