title: Evolutionary changes in the Leishmania eIF4F complex involve variations in the eIF4E-eIF4G interactions.
abstract: Translation initiation in eukaryotes is mediated by assembly of the eIF4F complex over the m(7)GTP cap structure at the 5'-end of mRNAs. This requires an interaction between eIF4E and eIF4G, two eIF4F subunits. The Leishmania orthologs of eIF4E are structurally diverged from their higher eukaryote counterparts, since they have evolved to bind the unique trypanosomatid cap-4 structure. Here, we characterize a key eIF4G candidate from Leishmania parasites (LeishIF4G-3) that contains a conserved MIF4G domain. LeishIF4G-3 was found to coelute with the parasite eIF4F subunits from an m(7)GTP-Sepharose column and to bind directly to LeishIF4E. In higher eukaryotes the eIF4E-eIF4G interaction is based on a conserved peptide signature [Y(X(4))Lphi], where X is any amino acid and Phi is a hydrophobic residue. A parallel eIF4E-binding peptide was identified in LeishIF4G-3 (20-YPGFSLDE-27). However, the binding motif varies extensively: in addition to Y20 and L25, binding strictly requires the presence of F23, whereas the hydrophobic amino acid (Phi) is dispensable. The LeishIF4E-LeishIF4G-3 interaction was also confirmed by nuclear magnetic resonance (NMR) studies. In view of these diversities, the characterization of the parasite eIF4E-eIF4G interaction may not only serve as a novel target for inhibiting Leishmaniasis but also provide important insight for future drug discovery.
authors.affiliation: Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Yoffe
authors.forename: Mélissa
authors.initials: M
authors.lastname: Léger
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zinoviev
authors.forename: Joanna
authors.initials: J
authors.lastname: Zuberek
authors.forename: Edward
authors.initials: E
authors.lastname: Darzynkiewicz
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.forename: Michal
authors.initials: M
authors.lastname: Shapira