EIF5

EIF5 Full Name

eukaryotic translation initiation factor 5

EIF5 Introduction

eIF5 (eukaryotic translation initiation factor 5) is a small but essential component of the machinery that translates messenger RNA into protein, acting at the moment when the ribosome selects the site at which protein synthesis begins. Translation initiation in eukaryotes is a multistep process in which a ribosome, guided by a set of initiation factors, scans an mRNA for the start codon; the accuracy of this selection determines both which protein is made and how much of it is produced. eIF5 enters the process at the point of start codon recognition, where it performs two critical tasks: it stimulates the hydrolysis of GTP bound to eIF2, the factor that delivers the initiator tRNA, and it promotes the release of the initiation factors so that the ribosome can begin elongation. By accelerating GTP hydrolysis only when the start codon has been correctly matched, eIF5 acts as a kinetic switch that couples the fidelity of start codon selection to the commitment to begin protein synthesis. In addition, eIF5 influences the efficiency of initiation on different mRNAs and can modulate the response of cells to stress, when the initiation machinery is reprogrammed to favor the translation of survival genes. The essential nature of eIF5 is underscored by the fact that it is conserved in all eukaryotes, and mutations that perturb its function alter the accuracy of translation initiation and cellular growth.

Figure 1. The structure of eIF5.

Two-Domain Architecture and the GAP Function of eIF5
eIF5 is composed of an N-terminal domain that carries the GTPase-activating protein (GAP) activity and a C-terminal domain that mediates interactions with other initiation factors.
The N-terminal domain accelerates the hydrolysis of GTP by eIF2, an otherwise slow reaction that is triggered only when the ribosome has recognized a start codon in the correct context.
The C-terminal domain of eIF5 contains binding sites for eIF2, eIF3, and eIF1, and through these interactions eIF5 is recruited to the ribosome early in initiation and released at the appropriate moment.
The eIF5 gene is located on human chromosome 14, and the protein is expressed in all tissues, reflecting its fundamental role in protein synthesis.
The interaction between eIF5 and eIF1 is particularly important: eIF1 promotes the scanning and proofreading of codons, while eIF5's GAP activity commits the ribosome to initiation, and the balance between the two factors sets the stringency of start codon selection.
In addition to its GAP function, eIF5 can bind GTP and has been reported to influence the overall rate of translation in ways that are still being defined.
Post-translational modifications of eIF5, including phosphorylation, modulate its activity and its interactions with the rest of the initiation machinery.

Start Codon Selection, Translational Control, and Cellular Stress
During translation initiation, the 43S preinitiation complex scans the 5' untranslated region of an mRNA for an AUG start codon, and the GTPase-activating function of eIF5 ensures that GTP hydrolysis, and hence the commitment to elongation, occurs only at the correct codon.
The competition between eIF5 and eIF1 determines the accuracy of initiation: increasing eIF5 activity biases initiation toward codons that match the start codon consensus poorly, whereas increasing eIF1 restrains premature commitment.
By influencing the stringency of start codon selection, eIF5 affects the translation of mRNAs with non-optimal start contexts, many of which encode regulatory proteins, so that changes in eIF5 levels alter the expression of specific gene products without globally changing protein synthesis.
Under stress conditions, the phosphorylation of eIF2 reduces the availability of the initiator tRNA complex and paradoxically increases the translation of stress-response mRNAs; eIF5 participates in these adjustments by modulating the GTPase reaction.
Because cancer cells depend on high rates of protein synthesis, the translation initiation machinery, including eIF5, is being investigated as a target for anticancer therapy.
Studies of eIF5 thus illuminate the fundamental question of how ribosomes choose where to begin protein synthesis and how this choice is regulated to meet the needs of the cell.

Alternate Names for EIF5

EIF5; eukaryotic translation initiation factor 5; eIF-5; EIF-5A;