Dynamics and structural features of the eEF1A1 and eEF1A2 paralogs

The translation elongation factors eEF1A1 and eEF1A2 share 97% sequence similarity and perform similar roles in translation but exhibit mutually exclusive expression patterns in human tissues. Despite their high homology, they are linked to different diseases, likely due to paralog-specific interactions with distinct protein partners. The underlying reasons for these differences remain unclear. Here, using a combination of HDX-MS, MD, and SAXS approaches, we demonstrate that eEF1A1 and eEF1A2 exhibit distinct structural dynamics, leading to different structural organizations. eEF1A2 is a compact, stably folded protein, whereas eEF1A1 adopts multiple conformational states, including the opening and closing of the conformational space between domains D1 and D3, as well as significant internal and external dynamics of domain D2. These dynamics facilitate protein dimerization in eEF1A1, contrasting with eEF1A2, which apparently remains monomeric in solution, challenging previous X-ray crystallography findings. These data provide molecular insight into the functional differences between the highly homologous translation factors eEF1A1 and eEF1A2, potentially explaining their paralog-specific nontranslational roles and distinct contributions to human diseases.