Nucleic Acids Research Advance Access originally published online on March 24, 2009
Nucleic Acids Research 2009 37(10):3243-3253; doi:10.1093/nar/gkp190
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Nucleic Acids Research, 2009, Vol. 37, No. 10 3243-3253
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Evolutionary changes in the Leishmania eIF4F complex involve variations in the eIF4E–eIF4G interactions
1Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel, 2Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA and 3Department of Biophysics, Institute for Experimental Physics, University of Warsaw, Warsaw, Poland
*To whom correspondence should be addressed. Tel: +972 8 647663 (office), +972 8 6461806 (lab); Fax: +972 8 6461710; Email: shapiram{at}bgu.ac.il
Received January 13, 2009. Revised March 9, 2009. Accepted March 9, 2009.
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 m7GTP-Sepharose column and to bind directly to LeishIF4E. In higher eukaryotes the eIF4E-eIF4G interaction is based on a conserved peptide signature [Y(X4)L
], where X is any amino acid and 
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 () 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.