Two structurally atypical HEAT domains in the C-terminal portion of human eIF4G support binding to eIF4A and Mnk1.
The X-ray structure of the C-terminal region of human eukaryotic translation initiation factor 4G (eIF4G) has been determined at 2.2 A resolution, revealing two atypical HEAT-repeat domains. eIF4G recruits various translation factors and the 40S ribosomal subunit to the mRNA 5' end. In higher eukaryotes, the C terminus of eIF4G (4G/C) supports translational regulation by recruiting eIF4A, an RNA helicase, and Mnk1, the kinase responsible for phosphorylating eIF4E. Structure-guided surface mutagenesis and protein-protein interaction assays were used to identify binding sites for eIF4A and Mnk1 within the HEAT-repeats of 4G/C. p97/DAP5, a translational modulator homologous to eIF4G, lacks an eIF4A binding site in the corresponding region. The second atypical HEAT domain of the 4G/C binds Mnk1 using two conserved aromatic/acidic-box (AA-box) motifs. Within the first AA-box, the aromatic residues contribute to the hydrophobic core of the domain, while the acidic residues form a negatively charged surface feature suitable for electrostatic interactions with basic residues in Mnk1.
Bellsolell
Lluís
L
Laboratories of Molecular Biophysics, The Rockefeller University, New York, New York 10021, USA.
Cho-Park
Park F
PF
Poulin
Francis
F
Sonenberg
Nahum
N
Burley
Stephen K
SK
D000595:Amino Acid Sequence; D024322:Amino Acids, Aromatic / Q000737:chemistry / Q000235:genetics; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D039601:Eukaryotic Initiation Factor-4A / Q000737:chemistry*; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D017434:Protein Structure, Tertiary
D024322:Amino Acids, Aromatic; D039603:Eukaryotic Initiation Factor-4G; D047908:Intracellular Signaling Peptides and Proteins; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases; D039601:Eukaryotic Initiation Factor-4A