Starting at the Beginning, Middle, and End: Translation Initiation in Eukaryotes

• Published in: Cell Vol. 89; no. 6; pp. 831 - 838
• Main Authors: Sachs, Alan B, Sarnow, Peter, Hentze, Matthias W
• Format: Book Review Journal Article
• Language: English
• Published: United States Elsevier Inc 13-06-1997
• Subjects: Eukaryotic Cells - physiology; Gene Expression Regulation - physiology; Protein Biosynthesis - genetics; RNA, Messenger - physiology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)80268-8

In both prokaryotes and eukaryotes, ribosomes are recruited to mRNAs in a sequential, multistep process. In eukaryotes, following the recruitment of the small ribosomal subunit to the mRNA, the mRNA sequence is scanned and the small subunit is placed at the initiation codon. After this, the joining of the large ribosomal subunit to the mRNA completes the assembly of the ribosome. In spite of the similarities, there are large differences between prokaryotes and eukaryotes in how these essential features are enacted. In particular, while the recruitment of the small ribosomal subunit to mRNA in prokaryotes is primarily directed by the basepairing between the 16S rRNA and the Shine-Dalgarno sequence on mRNA, the recruitment of the small ribosomal subunit to mRNA in eukaryotes is primarily directed by protein-protein and protein-RNA interactions. The recruitment of the 43S small ribosomal subunit complex (i.e., the 40S subunit and its associated initiation factors) to eukaryotic mRNA has historically been depicted as resulting from interactions between a limited set of translation initiation factors. One of these factors, eIF3, is a 40S subunit-associated factor comprised of at least 8 subunits in mammalian cells that interacts with the mRNA-associated initiation factor eIF4F. As a result, much past and recent work has focused on the interactions of eIF4F with mRNA and eIF3. eIF4F in all eukaryotic cells consists of two core subunits. These are the mRNA cap binding protein eIF4E and the large subunit eIF4G. Recent work on eIF4G has revealed that it contacts eIF3 via its C-terminal domain, while its N-terminal domain is responsible for its interaction with eIF4E. The modular nature of eIF4G has allowed for the formulation of a working model by which small ribosomal subunits are recruited to mRNA via the simultaneous association of eIF4G with both eIF4E and eIF3. Current models of how eIF4F is bound to the mRNA focus on the interaction of its eIF4E subunit with the mRNA cap structure. However, studies on the mechanisms by which an internal ribosome entry site (IRES) and the poly(A) tail on mRNA stimulate 40S subunit recruitment suggest that there are alternative ways to recruit the 43S complex to the mRNA. As a result of these studies, which are covered in more detail below, these current models fail to fully explain this early stage of translation initiation. This review will discuss recent findings that implicate different ways by which the 40S small ribosomal subunit can be recruited to eukaryotic mRNA and the various ways this recruitment step can be regulated. It will then present an integrated model of the 40S subunit recruitment step.