title: Structural basis for nematode eIF4E binding an m(2,2,7)G-Cap and its implications for translation initiation.
abstract: Metazoan spliced leader (SL) trans-splicing generates mRNAs with an m(2,2,7)G-cap and a common downstream SL RNA sequence. The mechanism for eIF4E binding an m²²⁷G-cap is unknown. Here, we describe the first structure of an eIF4E with an m(2,2,7)G-cap and compare it to the cognate m⁷G-eIF4E complex. These structures and Nuclear Magnetic Resonance (NMR) data indicate that the nematode Ascaris suum eIF4E binds the two different caps in a similar manner except for the loss of a single hydrogen bond on binding the m(2,2,7)G-cap. Nematode and mammalian eIF4E both have a low affinity for m(2,2,7)G-cap compared with the m⁷G-cap. Nematode eIF4E binding to the m⁷G-cap, m(2,2,7)G-cap and the m(2,2,7)G-SL 22-nt RNA leads to distinct eIF4E conformational changes. Additional interactions occur between Ascaris eIF4E and the SL on binding the m(2,2,7)G-SL. We propose interactions between Ascaris eIF4E and the SL impact eIF4G and contribute to translation initiation, whereas these interactions do not occur when only the m(2,2,7)G-cap is present. These data have implications for the contribution of 5'-UTRs in mRNA translation and the function of different eIF4E isoforms.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Weizhi
authors.initials: W
authors.lastname: Liu
authors.forename: Marzena
authors.initials: M
authors.lastname: Jankowska-Anyszka
authors.forename: Karolina
authors.initials: K
authors.lastname: Piecyk
authors.forename: Laura
authors.initials: L
authors.lastname: Dickson
authors.forename: Adam
authors.initials: A
authors.lastname: Wallace
authors.forename: Anna
authors.initials: A
authors.lastname: Niedzwiecka
authors.forename: Janusz
authors.initials: J
authors.lastname: Stepinski
authors.forename: Ryszard
authors.initials: R
authors.lastname: Stolarski
authors.forename: Edward
authors.initials: E
authors.lastname: Darzynkiewicz
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kieft
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.forename: David N M
authors.initials: DN
authors.lastname: Jones
authors.forename: Richard E
authors.initials: RE
authors.lastname: Davis
mesh_terms: D000818:Animals; D017165:Ascaris suum; D015226:Dinucleoside Phosphates / Q000737:chemistry; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry* / Q000378:metabolism; D015801:Helminth Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D010442:Peptide Chain Initiation, Translational; D011485:Protein Binding; D011487:Protein Conformation; D012314:RNA Cap Analogs / Q000737:chemistry*; D020038:RNA, Spliced Leader / Q000737:chemistry
chemical_list: D015226:Dinucleoside Phosphates; D039561:Eukaryotic Initiation Factor-4E; D015801:Helminth Proteins; D012314:RNA Cap Analogs; D020038:RNA, Spliced Leader; C062229:7-methyl-diguanosine triphosphate