40S recruitment in the absence of eIF4G/4A by EMCV IRES refines the model for translation initiation on the archetype of Type II IRESs

Nathalie Chamond (1) , Jules Deforges (1) , Nathalie Ulryck (1) , Bruno Sargueil (1)

1 LCRB - UMR 8015 - Laboratoire de cristallographie et RMN biologiques

Initiation of translation on Type II IRESs, such as those of EMCV and FMDV viruses, has been well documented in the recent years. For EMCV, the cur-rent model argues for a mechanism in which the key interaction necessary for the pre-initiation com-plex recruitment is eIF4G binding to the central J-K domains of EMCV-IRES. Here we demonstrate that, in contrast with the current model, the molecular mechanism of EMCV-IRES involves direct recruit-ment of the 40S subunit. Importantly, we identified a specific structural element that prevents the cor-rect positioning of the initiation codon in the close vicinity of the ribosomal P site. This work clarifies how this interaction could not be anticipated by ear-lier studies and allows us to propose a new model for initiation complex assembly on EMCV-IRES. The role attributed to eIF4G/4A can thus be refined as stabilizing/promoting the conformational changes that are necessary for IRES function, thus resembling the role conventionally assigned to ITAFs. This raises the interesting possibility that IRESs are primarily ri-bosome binders, some of which having partly lost the ability to fold into the active structure without the help of proteins.

Domaines: Sciences du Vivant [q-bio]

Nathalie Chamond, Jules Deforges, Nathalie Ulryck, Bruno Sargueil. 40S recruitment in the absence of eIF4G/4A by EMCV IRES refines the model for translation initiation on the archetype of Type II IRESs. Nucleic Acids Research, 2014, 42, pp.10373 - 10384. ⟨10.1093/nar/gku720⟩. ⟨hal-01075147⟩