The Eukaryotic Translation Initiation Factors eIF1 and eIF1A Induce an Open Conformation of the 40S Ribosome

Passmore, Lori A.; Schmeing, T.M.; Maag, David; Applefield, Drew; Acker, Michael G.; Algire, Mikkel A.; Lorsch, Jon R.; Ramakrishnan, V.

doi:10.1016/j.molcel.2007.03.018

Cited by 295 publications

(373 citation statements)

References 47 publications

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“…Moreover, the purpose of binding of the Hbs1 NTD to this region may indeed be to induce these changes. Interestingly, similar conformational changes involving h16 and rpS3 are also induced by binding to the 40S subunit of the initiation factors eIF1 and eIF1A (41), and the structurally distinct internal ribosomal entry sites (IRESs) of hepatitis C virus and cricket paralysis virus (25,42). In the case of these 40S initiation complexes, conformational changes involving h16 and rpS3 are concomitant with the opening of the mRNA entry channel "latch" on the intersubunit side, which is formed by h18 in the body and h34 and rpS3 in the neck of the 40S subunit.…”

Section: Discussionmentioning

confidence: 95%

Cryo-EM structure of the mammalian eukaryotic release factor eRF1–eRF3-associated termination complex

Taylor

Unbehaun

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Eukaryotic translation termination results from the complex functional interplay between two eukaryotic release factors, eRF1 and eRF3, and the ribosome, in which GTP hydrolysis by eRF3 couples codon recognition with peptidyl-tRNA hydrolysis by eRF1. Here, using cryo-electron microscopy (cryo-EM) and flexible fitting, we determined the structure of eRF1-eRF3-guanosine 5′- [β,γ-imido] triphosphate (GMPPNP)-bound ribosomal pretermination complex (pre-TC), which corresponds to the initial, pre-GTP hydrolysis stage of factor attachment. Our results show that eukaryotic translation termination involves a network of interactions between the two release factors and the ribosome. Our structure provides mechanistic insight into the coordination between GTP hydrolysis by eRF3 and subsequent peptide release by eRF1.T ermination of translation occurs when a ribosome reaches the end of the coding region and a stop codon (UAA, UAG, or UGA) enters the aminoacyl tRNA binding site (A site), leaving peptidyl-tRNA in the peptidyl tRNA binding site (P site). It entails stop codon recognition by specialized release factors followed by hydrolysis of peptidyl-tRNA. In eukaryotes, termination is mediated by the concerted action of two directly interacting release factors, eRF1 and eRF3. eRF1 is responsible for stop codon recognition and inducing hydrolysis of peptidyl-tRNA, whereas eRF3, a ribosome-dependent GTPase, strongly stimulates peptide release by eRF1 in a GTP-dependent manner (for review, see ref. 1).eRF1 also participates in ribosome recycling: after peptide release it remains associated with the ribosome and together with ATP-binding cassette sub-family E member 1 (ABCE1) promotes splitting the ribosome into free 60S and tRNA/mRNA-associated 40S subunits (2). eRF1 and eRF3 have paralogs, Dom34 (yeast)/ Pelota (mammals) and Hbs1, respectively, which do not participate in termination but instead play a key role in No-go and nonstop decay surveillance mechanisms (e.g., see refs. 3, 4). Dom34/Pelota and Hbs1 do not induce peptide release in a mechanism similar to eRFs. Instead, they cooperate with ABCE1 to promote dissociation of stalled elongation complexes, which is accompanied by peptidyltRNA drop off (5-7). eRF1 comprises N-terminal (N), middle (M), and C-terminal (C) domains (8). The N domain is responsible for stop codon recognition, which is achieved through a 3D network of conserved residues that include apical TASNIKS (amino acid sequence: threonine-alanine-serine-asparagine-isoleucine-lysine-serine) and YxCxxxF motifs (e.g., refs. 9-12). Domain M contains the universally conserved GGQ motif, which is critical for triggering peptide release: as shown for prokaryotes, its placement into the peptidyl transferase center (PTC) causes rRNA rearrangement, allowing a water molecule to enter (for review, see ref. 13). The rigid core of domain C forms an α-β sandwich (8) that deviates from the standard form by the presence of a small insertion, which forms a minidomain (14). eRF3 consists of an N-terminal sequence (residues 1-...

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Section: Discussionmentioning

confidence: 95%

Cryo-EM structure of the mammalian eukaryotic release factor eRF1–eRF3-associated termination complex

Taylor

Unbehaun

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…14,26,30,31,47,69,71 One of the key features differentiating eukaryotic from prokaryotic ribosomes is the extent of protein-protein interactions on the ribosome surface. It is believed that this structural complexity is directly related to the evolution of the translation apparatus, including appearance of new translation factors and multiple sophisticated mechanisms of translation control that are absent in prokaryotic cells.…”

Section: Discussionmentioning

confidence: 99%

“…Poly(A)-binding protein (PABP) is believed to enforce a "closed loop" mRNA conformation via interaction with eIF4G. Following recognition of the start codon and eIF5-induced irreversible hydrolysis of eIF2- 26,27 However, the exact mechanism by which the mRNA threads through the narrow mRNA channel in the 40S ribosomal subunit remains a mystery. The 'open' scanningcompetent conformation of the 40S subunit allows sampling of non-AUG triplets during movement of the initiation complex, but does not lead to efficient codon-anticodon base pairing.…”

Section: Introductionmentioning

confidence: 99%

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

Ghosh

Komar

2015

Translation

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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.

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“…However, eukaryotic initiation factor 1 (eIF1) is pertinent. Dissociation of eIF1 from the ternary initiation complex (eIF2, GTP, and Met-tRNA i Met ) is a key step in initiation codon selection (27)(28)(29). Specifically, mutants in eIF1 that reduce its affinity to the ternary complex increase initiation at non-AUG codons.…”

Section: Discussionmentioning

confidence: 99%

uORFs with unusual translational start codons autoregulate expression of eukaryotic ornithine decarboxylase homologs

Ivanov

Loughran

Atkins

2008

Proc. Natl. Acad. Sci. U.S.A.

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In a minority of eukaryotic mRNAs, a small functional upstream ORF (uORF), often performing a regulatory role, precedes the translation start site for the main product(s). Here, conserved uORFs in numerous ornithine decarboxylase homologs are identified from yeast to mammals. Most have noncanonical evolutionarily conserved start codons, the main one being AUU, which has not been known as an initiator for eukaryotic chromosomal genes. The AUG-less uORF present in mouse antizyme inhibitor, one of the ornithine decarboxylase homologs in mammals, mediates polyamine-induced repression of the downstream main ORF. This repression is part of an autoregulatory circuit, and one of its sensors is the AUU codon, which suggests that translation initiation codon identity is likely used for regulation in eukaryotes.antizyme ͉ AUU ͉ non-AUG ͉ polyamines ͉ upstream ORF

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The Eukaryotic Translation Initiation Factors eIF1 and eIF1A Induce an Open Conformation of the 40S Ribosome

Cited by 295 publications

References 47 publications

Cryo-EM structure of the mammalian eukaryotic release factor eRF1–eRF3-associated termination complex

Cryo-EM structure of the mammalian eukaryotic release factor eRF1–eRF3-associated termination complex

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

uORFs with unusual translational start codons autoregulate expression of eukaryotic ornithine decarboxylase homologs

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