Topology and regulation of the human eIF4A/4G/4H helicase complex in translation initiation.
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.
Marintchev
Assen
A
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. amarint@bu.edu
Edmonds
Katherine A
KA
Marintcheva
Boriana
B
Hendrickson
Elthea
E
Oberer
Monika
M
Suzuki
Chikako
C
Herdy
Barbara
B
Sonenberg
Nahum
N
Wagner
Gerhard
G
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
C111495:EIF4H protein, human; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D012333:RNA, Messenger; D039601:Eukaryotic Initiation Factor-4A; D020365:RNA Helicases