Structural basis for LeishIF4E-1 modulation by an interacting protein in the human parasite Leishmania major

Nucleic Acids Res. 2018 Apr 20;46(7):3791-3801. doi: 10.1093/nar/gky194.


Leishmania parasites are unicellular pathogens that are transmitted to humans through the bite of infected sandflies. Most of the regulation of their gene expression occurs post-transcriptionally, and the different patterns of gene expression required throughout the parasites' life cycle are regulated at the level of translation. Here, we report the X-ray crystal structure of the Leishmania cap-binding isoform 1, LeishIF4E-1, bound to a protein fragment of previously unknown function, Leish4E-IP1, that binds tightly to LeishIF4E-1. The molecular structure, coupled to NMR spectroscopy experiments and in vitro cap-binding assays, reveal that Leish4E-IP1 allosterically destabilizes the binding of LeishIF4E-1 to the 5' mRNA cap. We propose mechanisms through which Leish4E-IP1-mediated LeishIF4E-1 inhibition could regulate translation initiation in the human parasite.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Eukaryotic Initiation Factor-4E / chemistry*
  • Eukaryotic Initiation Factor-4E / genetics
  • Gene Expression Regulation / genetics
  • Humans
  • Leishmania major / genetics*
  • Leishmania major / pathogenicity
  • Leishmaniasis, Cutaneous / genetics*
  • Leishmaniasis, Cutaneous / parasitology
  • Protein Biosynthesis*
  • Structure-Activity Relationship


  • Eukaryotic Initiation Factor-4E