eIF3: a versatile scaffold for translation initiation complexes

Translation initiation in eukaryotes depends on many eukaryotic initiation factors (eIFs) that stimulate both recruitment of the initiator tRNA, Met-tRNAiMet, and mRNA to the 40S ribosomal subunit and subsequent scanning of the mRNA for the AUG start codon. The largest of these initiation factors, the eIF3 complex, organizes a web of interactions among several eIFs that assemble on the 40S subunit and participate in the different reactions involved in translation. Structural analysis suggests that eIF3 performs this scaffolding function by binding to the 40S subunit on its solvent-exposed surface rather than on its interface with the 60S subunit, where the decoding sites exist. This location of eIF3 seems ideally suited for its other proposed regulatory functions, including reinitiating translation on polycistronic mRNAs and acting as a receptor for protein kinases that control protein synthesis. Translation initiation in eukaryotes depends on many eukaryotic initiation factors (eIFs) that stimulate both recruitment of the initiator tRNA, Met-tRNAiMet, and mRNA to the 40S ribosomal subunit and subsequent scanning of the mRNA for the AUG start codon. The largest of these initiation factors, the eIF3 complex, organizes a web of interactions among several eIFs that assemble on the 40S subunit and participate in the different reactions involved in translation. Structural analysis suggests that eIF3 performs this scaffolding function by binding to the 40S subunit on its solvent-exposed surface rather than on its interface with the 60S subunit, where the decoding sites exist. This location of eIF3 seems ideally suited for its other proposed regulatory functions, including reinitiating translation on polycistronic mRNAs and acting as a receptor for protein kinases that control protein synthesis. Pre-initiation complex comprising the 40S subunit, TC, eIF1, eIF1A, eIF3 and eIF5. 43S PIC is so-called owing to its sedimentation velocity. Pre-initiation complex comprising a 43S PIC bound to mRNA. Single subunit factor that binds near the 40S subunit P-site. eIF1 enhances MFC assembly (in yeast), stimulates 43S PIC assembly and scanning, and promotes AUG selection by impeding GTP hydrolysis and release of Pi from eIF2–GDP–Pi at non-AUG codons. eIF1 is released from the P-site on AUG recognition. Single subunit factor thought to bind in the A-site of the 40S subunit. eIF1A stimulates 43S PIC assembly, scanning and AUG recognition. Heterotrimeric initiation factor (comprising subunits α, β and γ) that delivers Met-tRNAiMet to the 40S subunit in a ternary complex with GTP to form the 43S PIC. eIF2 stimulates MFC assembly (in yeast) and mRNA recruitment to the 43S PIC, and functions in AUG recognition during scanning. Guanine nucleotide exchange factor for eIF2 that recycles eIF2–GDP to eIF2–GTP to enable TC formation and another round of initiation. eIF2B is inhibited by phosphorylation of eIF2 on its α subunit by GCN2 and other eIF2α kinases. Single subunit factor that stimulates the ATP-dependent RNA helicase activity of eIF4A and interacts with eIF3. Heterotrimeric initiation factor comprising the m7G-cap-binding protein eIF4E, the ATP-dependent RNA helicase eIF4A, and the scaffold subunit eIF4G. Functions in mRNA recruitment to the 43S PIC (to produce the 48S PIC), scanning and AUG recognition. eIF4G has binding sites for PABP, eIF4E, eIF4A, eIF3 (in mammals) and eIF5 (in budding yeast). GTPase-activating protein for eIF2. eIF5 is required for GTP hydrolysis by TC on AUG recognition, is a prerequisite for association of the 60S subunit, and stimulates MFC assembly, 43S PIC formation and mRNA recruitment (possibly via interaction with eIF4G) in yeast. General control nonderepressible phenotype of mutations that prevents induction of translation of GCN4 mRNA and transcription of amino acid biosynthetic genes regulated by GCN4 under general amino acid control. General control nonderepressible 2. GCN2 is a protein kinase that phosphorylates eIF2 on its α subunit under conditions of amino acid starvation to inhibit recycling of eIF2–GDP to eIF2–GTP by eIF2B, which reduces TC formation and (in budding yeast) induces translation of GCN4 mRNA. Transcriptional activator of amino acid biosynthetic genes subject to general amino acid control. General control derepressed phenotype of mutations that confer constitutive derepression of translation of GCN4 mRNA and transcription of amino acid biosynthetic genes regulated by GCN4 under general amino acid control. Initiator methionyl tRNA charged with methionine. A multi-initiation factor complex comprising eIF3, eIF5, eIF1 and TC that can be isolated from budding yeast free of ribosomes and whose assembly stimulates or stabilizes formation of the 43S PIC. Mammalian target of rapamycin. mTOR is a protein kinase that stimulates translation initiation in response to adequate nutrients or insulin treatment by promoting phosphorylation of the eIF4E-binding protein, thereby preventing it from binding to eIF4E and from dissociating eIF4F. It also seems to stimulate binding of eIF3j to the eIF3 complex, eIF3–eIF4G association, and recruitment of eIF4B to the 48S PIC. Poly(A)-binding protein; binds to the poly(A) tail and to eIF4G, and stimulates mRNA recruitment to the 43S PIC. RNA recognition motif; contains conserved RNP1 and RNP2 motifs. S6 kinase 1. S6K1 is activated by mTOR and phosphorylates ribosomal protein S6 and eIF4B. Supressor of initiation codon mutation phenotype of mutations that confer increased initiation at an in-frame UUG codon in the beginning of the histidine biosynthetic gene HIS4, restoring the translation of HIS4 mRNA lacking the AUG start codon. Transactivator protein of plant caulimoviruses that interacts with eIF3g and stimulates reinitiation on polycistronic mRNAs. Ternary complex comprising eIF2 bound to GTP and Met-tRNAiMet. Short upstream open reading frame that regulates translation initiation of a second open reading frame downstream in the mRNA.