Inhibition of Eukaryotic Translation Initiation by the Marine Natural Product Pateamine A

• DOI: 10.1016/j.molcel.2005.10.008
• Publication Date: 2005-12-09T12:09:44Z
• Authors: Woon-Kai Low; Yongjun Dang; Tilman Schneider-...; Zonggao Shi; Nam Song Choi; William C. Merrick; Daniel Romo; Jun O. Liu
• Keywords: 0303 health sciences; Molecular Structure; Cell Biology; In Vitro Techniques; Thiazoles; 03 medical and health sciences; Eukaryotic Cells; Protein Biosynthesis; Eukaryotic Initiation Factor-4A; Epoxy Compounds; Humans; Macrolides; Eukaryotic Initiation Factors; Eukaryotic Initiation Factor-4G; Molecular Biology; HeLa Cells

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.