TY - JOUR
T1 - Evolutionary changes in the Leishmania eIF4F complex involve variations in the eIF4E-eIF4G interactions
AU - Yoffe, Yael
AU - Léger, Mélissa
AU - Zinoviev, Alexandra
AU - Zuberek, Joanna
AU - Darzynkiewicz, Edward
AU - Wagner, Gerhard
AU - Shapira, Michal
N1 - Funding Information:
US-Israel Binational Foundation (grant number 2007287 to M.S. and G.W.); the UNICEF/UNDP/World Bank/ WHO Special Programme for Research and Training in Tropical Diseases (to M.S.); the Israel Ministry of Health (grant number 5440 to M.S.); the National Institutes of Health (grant numbers CA68262 and GM47467 to G.W.); a post-doctoral fellowship from the Fonds de la Recherche en Santé du Québec (to M.L.); the Howard Hughes Medical Institute (grant number 55005604 to E.D.); the National Science Support Project 2008-2010 No. PBZ-MNiSW-07/I/2007 (to E.D.). Funding for open access charge: US-Israel Binational Foundation (grant number 2007287 to M.S. and G.W.), National Institutes of Health (grant number CA075879 to G.W.) and Howard Hughes Medical Institute (grant number 55005604 to E.D.).
PY - 2009/6/23
Y1 - 2009/6/23
N2 - Translation initiation in eukaryotes is mediated by assembly of the eIF4F complex over the m7GTP 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 m7 GTP-Sepharose column and to bind directly to LeishIF4E. In higher eukaryotes the eIF4E-eIF4G interaction is based on a conserved peptide signature [Y(X4)Lφ], where X is any amino acid and Φ 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 (Φ) 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.
AB - Translation initiation in eukaryotes is mediated by assembly of the eIF4F complex over the m7GTP 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 m7 GTP-Sepharose column and to bind directly to LeishIF4E. In higher eukaryotes the eIF4E-eIF4G interaction is based on a conserved peptide signature [Y(X4)Lφ], where X is any amino acid and Φ 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 (Φ) 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.
UR - http://www.scopus.com/inward/record.url?scp=67449093457&partnerID=8YFLogxK
U2 - 10.1093/nar/gkp190
DO - 10.1093/nar/gkp190
M3 - Article
AN - SCOPUS:67449093457
SN - 0305-1048
VL - 37
SP - 3243
EP - 3253
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 10
ER -