Crystal structure of the Trypanosoma cruzi EIF4E5 translation factor homologue in complex with mRNA cap-4

Lidia Watanabe Reolon (1, 2) , Sophie Vichier-Guerre (3) , Bruno Moisés de Matos (1, 2) , Laurence Dugué (3) , Tatiana Reichert da Silva Assunção (1) , Nilson Ivo Tonin Zanchin (1) , Sylvie S. Pochet (3) , Beatriz Gomes Guimarães (1)

1 ICC - Fiocruz Paraná - Instituto Carlos Chagas / Carlos Chagas Institute [Curitiba, Brésil]
2 IFPR - Instituto Federal Paraná
3 Chimie et Biocatalyse

Association of the initiation factor eIF4E with the mRNA cap structure is a key step for translation. Trypanosomatids present six eIF4E homologues, showing a low conservation and also differing significantly from the IF4Es of multicellular eukaryotes. On the mRNA side, while in most eukaryotes the mRNA contains cap-0 (7-methyl-GTP), the trypanosomatid mRNA features a cap-4, which is formed by a cap-0, followed by the AACU sequence containing 2'-O-ribose methylations and base methylations on nucleotides 1 and 4. The studies on eIF4E-cap-4 interaction have been hindered by the difficulty to synthesize this rather elaborated cap-4 sequence. To overcome this problem, we applied a liquid-phase oligonucleotide synthesis strategy and describe for the first time the crystal structure of a trypanosomatid eIF4E (T. cruzi EIF4E5) in complex with cap-4. The TcEIF4E5-cap-4 structure allowed a detailed description of the binding mechanism, revealing the interaction mode for the AACU sequence, with the bases packed in a parallel stacking conformation and involved, together with the methyl groups, in hydrophobic contacts with the protein. This binding mechanism evidences a distinct cap interaction mode in comparison with previously described eIF4E structures and may account for the difference of TcEIF4E5-cap-4 dissociation constant in comparison with other eIF4E homologues.

Domaines: Biologie structurale [q-bio.BM]; Biochimie, Biologie Moléculaire; Chimie; Chimie organique

Lidia Watanabe Reolon, Sophie Vichier-Guerre, Bruno Moisés de Matos, Laurence Dugué, Tatiana Reichert da Silva Assunção, et al.. Crystal structure of the Trypanosoma cruzi EIF4E5 translation factor homologue in complex with mRNA cap-4. Nucleic Acids Research, 2019, ⟨10.1093/nar/gkz339⟩. ⟨pasteur-02127386⟩