On the Need to Tell Apart Fraternal Twins eEF1A1 and eEF1A2, and Their Respective Outfits

eEF1A1 and eEF1A2 are paralogous proteins whose presence in most normal eukaryotic cells is mutually exclusive and developmentally regulated. Often described in the scientific literature under the collective name eEF1A, which stands for eukaryotic elongation factor 1A, their best known activity (in a monomeric, GTP-bound conformation) is to bind aminoacyl-tRNAs and deliver them to the A-site of the 80S ribosome. However, both eEF1A1 and eEF1A2 are endowed with multitasking abilities (sometimes performed by homo- and heterodimers) and can be located in different subcellular compartments, from the plasma membrane to the nucleus. Given the high sequence identity of these two sister proteins and the large number of post-translational modifications they can undergo, we are often confronted with the dilemma of discerning which is the particular proteoform that is actually responsible for the ascribed biochemical or cellular effects. We argue in this review that acquiring this knowledge is essential to help clarify, in molecular and structural terms, the mechanistic involvement of these two ancestral and abundant G proteins in a variety of fundamental cellular processes other than translation elongation. Of particular importance for this special issue is the fact that several de novo heterozygous missense mutations in the human EEF1A2 gene are associated with a subset of rare but severe neurological syndromes and cardiomyopathies.

Automated summary

eEF1A1 and eEF1A2 are paralogous proteins with multitasking abilities, whose presence in normal eukaryotic cells is mutually exclusive and regulated. The high sequence identity and post-translational modifications of these proteins pose challenges in discerning their specific proteoforms responsible for cellular effects. Their involvement in fundamental cellular processes beyond translation elongation is crucial, especially in the context of genetic mutations linked to neurological syndromes and cardiomyopathies.