Coordinated Movements of Eukaryotic Translation Initiation Factors eIF1, eIF1A, and eIF5 Trigger Phosphate Release from eIF2 in Response to Start Codon Recognition by the Ribosomal Preinitiation Complex*

Nanda, Jagpreet S.; Saini, Adesh K.; Munoz, Antonio; Hinnebusch, Alan G.; Lorsch, Jon R.

doi:10.1074/jbc.m112.440693

Cited by 80 publications

(142 citation statements)

References 44 publications

Supporting

Mentioning

127

Contrasting

Unclassified

Order By: Relevance

“…28,63,64 It also plays a role, along with eIF5B, in ensuring proper subunit joining and formation of elongation-competent 80S ribosomes. 28,63,64 Hydroxyl radical probing and structural modeling involving eIF1A and Tetrahymena thermophila 40S ribosomal subunits (based on bacterial 30S:IF1 complex information) at »3.9A suggested that eIF1A resides near the A-site and makes contacts with eukaryotespecific proteins eS27 and eS30 as well as conserved protein uS12 which harbors eukaryote-specific extensions. 15,65 However, direct involvement of uS12 eukaryote-specific extensions in eIF1A binding has not been proven yet.…”

Section: E999576-6mentioning

confidence: 99%

Eukaryote-specific extensions in ribosomal proteins of the small subunit: Structure and function

Ghosh

Komar

2015

Translation

View full text Add to dashboard Cite

Keywords: conserved ribosomal proteins, eukaryotic/yeast ribosome, eukaryote-specific extensions, eukaryotic translation initiation factors, protein synthesis, small ribosomal subunitHigh-resolution structures of yeast ribosomes have improved our understanding of the architecture and organization of eukaryotic rRNA and proteins, as well as eukaryote-specific extensions present in some conserved ribosomal proteins. Despite this progress, assignment of specific functions to individual proteins and/or eukaryotespecific protein extensions remains challenging. It has been suggested that eukaryote-specific extensions of conserved proteins from the small ribosomal subunit may facilitate eukaryote-specific reactions in the initiation phase of protein synthesis. This review summarizes emerging data describing the structural and functional significance of eukaryotespecific extensions of conserved small ribosomal subunit proteins, particularly their possible roles in recruitment and spatial organization of eukaryote-specific initiation factors.

show abstract

Section: E999576-6mentioning

confidence: 99%

Eukaryote-specific extensions in ribosomal proteins of the small subunit: Structure and function

Ghosh

Komar

2015

Translation

View full text Add to dashboard Cite

show abstract

“…One possibility would be that eIF2β-S264Y prevents the eIF2β-NTT from releasing eIF1 and binding to the eIF5-CTD, which should impede dissociation of eIF1 from the PIC (Fig. 1A; Nanda et al 2013). However, interaction between the eIF2β zinc-binding domain and its NTT has not been reported, and it is also unclear why this would happen at AUG, but not at UUG, start codons.…”

Section: Martin-marcos Et Almentioning

confidence: 99%

“…Thus, eIF1 performs a dual function in the scanning mechanism of promoting rapid TC loading in the P OUT configuration while impeding rearrangement to the more stable P IN state until an AUG codon is recognized by Met-tRNA i (Fig. 1A;Hinnebusch 2011;Nanda et al 2013). …”

Section: Introductionmentioning

confidence: 99%

“…(Below) The arrows summarize that eIF1 and the eIF1A SE elements promote P OUT and block the transition to the P IN state, whereas the scanning inhibitor (SI) element in the NTT of eIF1A stabilizes the P IN state. (Adapted from Hinnebusch and Lorsch 2012;Nanda et al 2013. ) MS---IENLKSFDPFADTGDDE---TATSNY--IHIRIQQRNGRKTLTTVQGVPEEYDLK 52 Ashbya MS---IENLKSFDPFADTGDDE---ASSSNY--IHIRIQQRNGRKTLTTVQGIPEEYDLK 52 Schizosaccharomy.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Enhanced eIF1 binding to the 40S ribosome impedes conformational rearrangements of the preinitiation complex and elevates initiation accuracy

Martín-Marcos

Nanda

Luna

et al. 2013

RNA

Self Cite

View full text Add to dashboard Cite

In the current model of translation initiation by the scanning mechanism, eIF1 promotes an open conformation of the 40S subunit competent for rapidly loading the eIF2·GTP·Met-tRNA i ternary complex (TC) in a metastable conformation (P OUT ) capable of sampling triplets entering the P site while blocking accommodation of Met-tRNA i in the P IN state and preventing completion of GTP hydrolysis (P i release) by the TC. All of these functions should be reversed by eIF1 dissociation from the preinitiation complex (PIC) on AUG recognition. We tested this model by selecting eIF1 Ssu − mutations that suppress the elevated UUG initiation and reduced rate of TC loading in vivo conferred by an eIF1 (Sui − ) substitution that eliminates a direct contact of eIF1 with the 40S subunit. Importantly, several Ssu − substitutions increase eIF1 affinity for 40S subunits in vitro, and the strongest-binding variant (D61G), predicted to eliminate ionic repulsion with 18S rRNA, both reduces the rate of eIF1 dissociation and destabilizes the P IN state of TC binding in reconstituted PICs harboring Sui − variants of eIF5 or eIF2. These findings establish that eIF1 dissociation from the 40S subunit is required for the P IN mode of TC binding and AUG recognition and that increasing eIF1 affinity for the 40S subunit increases initiation accuracy in vivo. Our results further demonstrate that the GTPase-activating protein eIF5 and β-subunit of eIF2 promote accuracy by controlling eIF1 dissociation and the stability of TC binding to the PIC, beyond their roles in regulating GTP hydrolysis by eIF2.

show abstract

“…Once AUG recognition and codon-anticodon base-pairing has been established, the eIF5 carboxy moiety promotes the dissociation of eIF1, together with inorganic phosphate derived from the GTP hydrolysis of the ternary complex (Cheung et al 2007;Luna et al 2012). In addition, the eIF1A carboxy terminus moves closer to the eIF5 amino terminus (Nanda et al 2013). This movement is coupled to eIF1 exit, which leaves the P site free and allows tighter binding of the initiator tRNA at this site.…”

Section: Introductionmentioning

confidence: 99%

Initiation codon selection is accomplished by a scanning mechanism without crucial initiation factors in Sindbis virus subgenomic mRNA

García-Moreno

Sanz

Carrasco

2014

RNA

View full text Add to dashboard Cite

Translation initiation of alphavirus subgenomic mRNA (sgmRNA) can occur in the absence of several initiation factors (eIFs) in infected cells; however, the precise translation mechanism is still poorly understood. In this study, we have examined the mechanism of initiation and AUG selection in Sindbis virus (SINV) sgmRNA. Our present findings suggest that sgmRNA is translated via a scanning mechanism, since the presence of a hairpin structure before the initiation codon hampers protein synthesis directed by this mRNA. In addition, translation is partially recovered when an in-frame AUG codon is placed upstream of this hairpin. This scanning process takes place without the participation of eIF4A and active eIF2. These results, combined with our findings through modifying the SINV sgmRNA leader sequence, do not support the possibility of a direct initiation from the start codon without previous scanning, or a shunting mechanism. Moreover, studies carried out with sgmRNAs containing two alternative AUG codons within a good context for translation reveal differences in AUG selection which are dependent on the cellular context and the phosphorylation state of eIF2α. Thus, initiation at the additional AUG is strictly dependent on active eIF2, whereas the genuine AUG codon can start translation following eIF2α inactivation. Collectively, our results suggest that SINV sgmRNA is translated by a scanning mechanism without the potential participation of crucial eIFs. A model is presented that explains the mechanism of initiation of mRNAs bearing two alternative initiation codons.

show abstract

Coordinated Movements of Eukaryotic Translation Initiation Factors eIF1, eIF1A, and eIF5 Trigger Phosphate Release from eIF2 in Response to Start Codon Recognition by the Ribosomal Preinitiation Complex*

Cited by 80 publications

References 44 publications

Eukaryote-specific extensions in ribosomal proteins of the small subunit: Structure and function

Eukaryote-specific extensions in ribosomal proteins of the small subunit: Structure and function

Enhanced eIF1 binding to the 40S ribosome impedes conformational rearrangements of the preinitiation complex and elevates initiation accuracy

Initiation codon selection is accomplished by a scanning mechanism without crucial initiation factors in Sindbis virus subgenomic mRNA

Contact Info

Product

Resources

About