Abstract
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.
Highlights
Protein synthesis is one of the most sophisticated biochemical processes in living cells and comprises the same steps in Eukarya, bacteria and archaea: initiation, elongation and termination-ribosome recycling notwithstanding
During the translation elongation step, the G protein known as the eukaryotic elongation factor 1A, in complex with GTP, binds to and delivers the aminoacyl-tRNA to the A-site of the 80S ribosome
Following hydrolysis of the ester bond linking β and γ phosphates in GTP, the guanine nucleotide exchange factor (GEF) eEF1B interacts with eukaryotic elongation factor 1A (eEF1A) to release it from the ribosome in its GDP-bound state, which adopts a different conformation and is thought to be involved in other functions, despite the often-assigned appellative of being “inactive” [3,4]. tRNA charging onto eEF1A and delivery to the ribosome is a highly efficient channeled process that requires additional factors [5], which together make up the so-called eEF1 complex, whose composition changes as the complexity of the eukaryotic organism increases [6]
Summary
Protein synthesis is one of the most sophisticated biochemical processes in living cells and comprises the same steps in Eukarya, bacteria and archaea: initiation, elongation and termination-ribosome recycling notwithstanding. Tyr and Lys100, which are spatially close to Asp and Phe98 This profusion of amino acids that are strictly conserved throughout evolution [34], and substituted due to missense mutations in children affected with severe neurodevelopmental disorders (Table 2), appears to support a role for the eEF1A2 dimer (Figure 2) in cellular functions that are necessarily distinct from that of delivering tRNA to the ribosome. A physiological pH increase promotes the GTP-dependent binding of eEF1A to aa-tRNAs, changing its spatial distribution and upregulating protein translation [94] This dynamic functional switch is likely to be driven by a conformational transition brought about by what can be considered [95] a PTM by protons, i.e., an alteration in the charge of crucial amino acid side chains These structural cues pave the way for future experimental and modeling studies that will shed more light on the intricacies of eEF1A1/2–membrane interactions
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