title: Topology and regulation of the human eIF4A/4G/4H helicase complex in translation initiation.
abstract: The RNA helicase eIF4A plays a key role in unwinding of mRNA and scanning during translation initiation. Free eIF4A is a poor helicase and requires the accessory proteins eIF4G and eIF4H. However, the structure of the helicase complex and the mechanisms of stimulation of eIF4A activity have remained elusive. Here we report the topology of the eIF4A/4G/4H helicase complex, which is built from multiple experimentally observed domain-domain contacts. Remarkably, some of the interactions are continuously rearranged during the ATP binding/hydrolysis cycle of the helicase. We show that the accessory proteins modulate the affinity of eIF4A for ATP by interacting simultaneously with both helicase domains and promoting either the closed, ATP-bound conformation or the open, nucleotide-free conformation. The topology of the complex and the spatial arrangement of the RNA-binding surfaces offer insights into their roles in stimulation of helicase activity and the mechanisms of mRNA unwinding and scanning.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. amarint@bu.edu
authors.forename: Assen
authors.initials: A
authors.lastname: Marintchev
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Edmonds
authors.forename: Boriana
authors.initials: B
authors.lastname: Marintcheva
authors.forename: Elthea
authors.initials: E
authors.lastname: Hendrickson
authors.forename: Monika
authors.initials: M
authors.lastname: Oberer
authors.forename: Chikako
authors.initials: C
authors.lastname: Suzuki
authors.forename: Barbara
authors.initials: B
authors.lastname: Herdy
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
mesh_terms: D039601:Eukaryotic Initiation Factor-4A / Q000737:chemistry / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D019906:Nuclear Magnetic Resonance, Biomolecular; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D020365:RNA Helicases / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C111495:EIF4H protein, human; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D012333:RNA, Messenger; D039601:Eukaryotic Initiation Factor-4A; D020365:RNA Helicases