Protein Synthesis Initiation in Eukaryotic Cells

Abstract

This review summarizes our current understanding of the major pathway for the initiation phase of protein synthesis in eukaryotic cells, with a focus on recent advances. We describe the major scanning or messenger RNA (mRNA) mG cap-dependent mechanism, which is a highly coordinated and stepwise regulated process that requires the combined action of at least 12 distinct translation factors with initiator transfer RNA (tRNA), ribosomes, and mRNAs. We limit our review to studies involving either mammalian or budding yeast cells and factors, as these represent the two best-studied experimental systems, and only include a reference to other organisms where particular insight has been gained. We close with a brief description of what we feel are some of the major unknowns in eukaryotic initiation.

Regulation of translation initiation factor eIF2B at the hub of the integrated stress response

“…eIF2 shown is taken from a larger partial yeast PIC structure (PDB file 3JAP) (Llacer et al, 2015). (b) Cartoon image indicating major protein interaction partners important in the ISR eIFs 4A and 4B help eliminate mRNA secondary structure to promote PIC-mRNA interactions (Hinnebusch, 2014;Merrick & Pavitt, 2018). Recent evidence from in vitro reactions suggests that the PIC is threaded on to the mRNA so that tRNA i Met can recognize AUG codons close to the 5 0 cap (Kumar, Hellen, & Pestova, 2016).…”

“…The resulting eIF2-GDP has significantly reduced affinity for tRNA i Met , prompting eIF2-GDP release from tRNA i Met and the PIC. These events likely commit the ribosome to initiating at the bound AUG by prompting 60S joining so that the translation elongation phase can proceed (Hinnebusch, 2014;Hinnebusch, 2017;Merrick & Pavitt, 2018). Released factors participate in new rounds of initiation on the same or other mRNAs.…”

Translational Control under Stress: Reshaping the Translatome

“…Two classes of mTORC1 targets are especially relevant for translation regulation under stress. The first includes the family of small phosphoproteins termed 4EBPs, which directly bind to eIF4E . Under optimal conditions, mTORC1 constitutively phosphorylates 4EBPs and their phosphorylated variants (p‐4EBPs) cannot bind eIF4E.…”

“…The first includes the family of small phosphoproteins termed 4EBPs, which directly bind to eIF4E. [31] Under optimal conditions, mTORC1 constitutively phosphorylates 4EBPs and their phosphorylated variants (p-4EBPs) cannot bind eIF4E. In response to stress, mTORC1 is inactivated and p-4EBPs become dephosphorylated.…”

Decapping enzymes STOP “cancer” ribosomes in their tracks

“…It has long been appreciated that misregulation of protein synthesis is a hallmark and driving force in many cancers (Robichaud et al, 2018). The rate-limiting step of protein synthesis for the majority of mRNA transcripts in the cell is thought to be cap-dependent translation initiation, during which (eukaryotic) initiation factors (eIFs) recruit the ribosome to mRNA using its 5 0 terminal m7G cap structure (Merrick & Pavitt, 2018). Overexpression of initiation factors correlates with enhanced translational efficiency of oncogenic mRNAs and transformation of cells (Chu et al, 2016).…”