The many roles of the eukaryotic elongation factor 1 complex

Abstract

The vast majority of proteins are believed to have one specific function. Throughout the course of evolution, however, some proteins have acquired additional functions to meet the demands of a complex cellular milieu. In some cases, changes in RNA or protein processing allow the cell to make the most of what is already encoded in the genome to produce slightly different forms. The eukaryotic elongation factor 1 (eEF1) complex subunits, however, have acquired such moonlighting functions without alternative forms. In this article, we discuss the canonical functions of the components of the eEF1 complex in translation elongation as well as the secondary interactions they have with other cellular factors outside of the translational apparatus. The eEF1 complex itself changes in composition as the complexity of eukaryotic organisms increases. Members of the complex are also subject to phosphorylation, a potential modulator of both canonical and non-canonical functions. Although alternative functions of the eEF1A subunit have been widely reported, recent studies are shedding light on additional functions of the eEF1B subunits. A thorough understanding of these alternate functions of eEF1 is essential for appreciating their biological relevance.

Figure 1. Model of eEF1 complex

The variation in the organization of the eEF1 complex in different organisms illustrates the differences in the composition as well as the interactions of the various subunits. Domain I, the largest domain of eEF1A (gold) is the GTP binding domain. For the eEF1B subunits α (red) γ (blue) δ (green), the N and C terminal domains are indicated in darker and lighter shades respectively. Val RS (purple) interacts with the eEF1 complex in metazoans.

Figure 2. Location of mutations that affect non-canonical functions and known phosphorylation sites on eEF1A

eEF1A from S. cerevisiae is composed of three well-defined domains as determined from the co-crystal structure with the C terminus of eEF1Bα. Domain I (blue) binds GTP, domain II (red) is proposed to interact with the aminoacyl end of the aa-tRNA, and domains II and III (green) are linked to actin binding and bundling. eEF1Bα binds eEF1A in domains I and II. Colored spheres indicate mutations that affect the non-canonical functions of eEF1A. In domain I, Asp156Asn (purple) affects protein turnover. In domain II, Glu286Lys and Glu291Lys (cyan) affect nuclear transport. Mutations that affect actin organization, Asn305Ser, Asn329Ser, Phe308Lys and Ser405Pro, (yellow), are shown in domains II and III. Phosphorylation of Glu298 (the yeast equivalent of human Ser300) (orange) may lead to downregulation of translation. The figure was prepared with PyMol using Protein Data Bank (PDB) 1F60.

Figure 3. The role of eEF1A in minus strand synthesis of positive strand viral RNAs

Upon release of the viral RNA (green) into the cytoplasm, eEF1A (yellow) binds at the tRNA-like structure at the 3′-end of the RNA preventing the RNA-dependent RNA polymerase (RdRp, blue) from initiating minus strand synthesis. By inhibiting minus strand synthesis, eEF1A allows viral proteins to be synthesized first. Once sufficient RdRp is made, RdRp competes eEF1A off of the viral end allowing for minus strand synthesis to occur.