title: Crystal structure of the eIF4A-PDCD4 complex.
abstract: Tumor suppressor programmed cell death protein 4 (PDCD4) inhibits the translation initiation factor eIF4A, an RNA helicase that catalyzes the unwinding of secondary structure at the 5'-untranslated region of mRNAs and controls the initiation of translation. Here, we determined the crystal structure of the human eIF4A and PDCD4 complex. The structure reveals that one molecule of PDCD4 binds to the two eIF4A molecules through the two different binding modes. While the two MA3 domains of PDCD4 bind to one eIF4A molecule, the C-terminal MA3 domain alone of the same PDCD4 also interacts with another eIF4A molecule. The eIF4A-PDCD4 complex structure suggests that the MA3 domain(s) of PDCD4 binds perpendicular to the interface of the two domains of eIF4A, preventing the domain closure of eIF4A and blocking the binding of RNA to eIF4A, both of which are required events in the function of eIF4A helicase. The structure, together with biochemical analyses, reveals insights into the inhibition mechanism of eIF4A by PDCD4 and provides a framework for designing chemicals that target eIF4A.
authors.affiliation: National Creative Initiatives for Structural Biology and Department of Life Science, Pohang University of Science and Technology, Hyo-ja dong, San31, Pohang, KyungBook, South Korea.
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Chang
authors.forename: Yong Hyun
authors.initials: YH
authors.lastname: Cho
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Sohn
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Choi
authors.forename: Ahreum
authors.initials: A
authors.lastname: Kim
authors.forename: Young Chang
authors.initials: YC
authors.lastname: Kim
authors.forename: Sung Key
authors.initials: SK
authors.lastname: Jang
authors.forename: Yunje
authors.initials: Y
authors.lastname: Cho
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D053487:DEAD-box RNA Helicases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D053487:DEAD-box RNA Helicases