Evolutionary and genetic analyses of mitochondrial translation initiation factors identify the missing mitochondrial IF3 in S. cerevisiae

Atkinson, Gemma C.; Kuzmenko, Anton; Kamenski, Piotr; Vysokikh, Mikhail; Lakunina, V. A.; Tankov, Stoyan; Smirnova, Ekaterina; Soosaar, Andres; Tenson, Tanel; Hauryliuk, Vasili

doi:10.1093/nar/gks272

Cited by 40 publications

(66 citation statements)

References 91 publications

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“…E. coli complementation experiments have demonstrated that expression of plasmid-borne bovine mIF2, but not E. coli IF2 can support the viability of an E. coli strain lacking genomic copies of initiation factors IF2 and IF1 [27]. This result was interpreted in a model postulating that, despite a lack of homology to IF1 and twice smaller size [9], the insertion serves as a functional replacement of IF1. Subsequent structural studies demonstrated that the insertion shares the same binding pocket on the bacterial ribosome as IF1 [26], seemingly supporting the idea that it has evolved as an IF1 substitute.…”

Section: Mitochondrial Initiation Factor 2 (Mif2)mentioning

confidence: 99%

Mitochondrial translation initiation machinery: Conservation and diversification

et al. 2014

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The highly streamlined mitochondrial genome encodes almost exclusively a handful of transmembrane components of the respiratory chain complex. In order to ensure the correct assembly of the respiratory chain, the products of these genes must be produced in the correct stoichiometry and inserted into the membrane, posing a unique challenge to the mitochondrial translational system. In this review we describe the proteins orchestrating mitochondrial translation initiation: bacterial-like general initiation factors mIF2 and mIF3, as well as mitochondria-specific components – mRNA-specific translational activators and mRNA-nonspecific accessory initiation factors. We consider how the fast rate of evolution in these organelles has not only created a system that is divergent from that of its bacterial ancestors, but has led to a huge diversity in lineage specific mechanistic features of mitochondrial translation initiation among eukaryotes.

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Section: Mitochondrial Initiation Factor 2 (Mif2)mentioning

confidence: 99%

Mitochondrial translation initiation machinery: Conservation and diversification

et al. 2014

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“…Mitochondrial mRNAs lack Shine-Dalgarno elements that could facilitate their interaction with ribosomes, and it is unclear how translation initiation is accomplished. Mitochondria have homologs of bacterial initiation factors IF2 (the functional equivalent of bacterial IF1 and IF2 [27]) and IF3 [28–32]. In mammals, IF2-mt promotes the binding of the initiator formylmethionine-tRNA (fMet-tRNA) to the AUG codon at the ribosomal peptidyl-site [33].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial ribosomes in cancer

Kim

Maiti

Barrientos

2017

Seminars in Cancer Biology

146

120

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Mitochondria play fundamental roles in the regulation of life and death of eukaryotic cells. They mediate aerobic energy conversion through the oxidative phosphorylation (OXPHOS) system, and harbor and control the intrinsic pathway of apoptosis. As a descendant of a bacterial endosymbiont, mitochondria retain a vestige of their original genome (mtDNA), and its corresponding full gene expression machinery. Proteins encoded in the mtDNA, all components of the multimeric OXPHOS enzymes, are synthesized in specialized mitochondrial ribosomes (mitoribosomes). Mitoribosomes are therefore essential in the regulation of cellular respiration. Additionally, an increasing body of literature has been reporting an alternative role for several mitochondrial ribosomal proteins as apoptosis-inducing factors. No surprisingly, the expression of genes encoding for mitoribosomal proteins, mitoribosome assembly factors and mitochondrial translation factors is modified in numerous cancers, a trait that has been linked to tumorigenesis and metastasis. In this article, we will review the current knowledge regarding the dual function of mitoribosome components in protein synthesis and apoptosis and their association with cancer susceptibility and development. We will also highlight recent developments in targeting mitochondrial ribosomes for the treatment of cancer.

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“…Both IF3 and IF2 are also responsible for the fidelity of decoding the initiation AUG by fMet-tRNA Met f at the P site of 30S subunits (10). IF1 is universal (11) and essential for viability (12). It is the smallest factor, with 72 amino acid residues in Escherichia coli, and binds to the decoding center at the ribosomal A site (13).…”

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confidence: 99%

70S-scanning initiation is a novel and frequent initiation mode of ribosomal translation in bacteria

Yamamoto

Wittek

Gupta

et al. 2016

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

106

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According to the standard model of bacterial translation initiation, the small ribosomal 30S subunit binds to the initiation site of an mRNA with the help of three initiation factors (IF1-IF3). Here, we describe a novel type of initiation termed "70S-scanning initiation," where the 70S ribosome does not necessarily dissociate after translation of a cistron, but rather scans to the initiation site of the downstream cistron. We detailed the mechanism of 70S-scanning initiation by designing unique monocistronic and polycistronic mRNAs harboring translation reporters, and by reconstituting systems to characterize each distinct mode of initiation. Results show that 70S scanning is triggered by fMet-tRNA and does not require energy; the Shine-Dalgarno sequence is an essential recognition element of the initiation site. IF1 and IF3 requirements for the various initiation modes were assessed by the formation of productive initiation complexes leading to synthesis of active proteins. IF3 is essential and IF1 is highly stimulating for the 70S-scanning mode. The task of IF1 appears to be the prevention of untimely interference by ternary aminoacyl (aa)-tRNA•elongation factor thermo unstable (EF-Tu)•GTP complexes. Evidence indicates that at least 50% of bacterial initiation events use the 70S-scanning mode, underscoring the relative importance of this translation initiation mechanism.protein synthesis | ribosomal functions | translational initiation | 30S-binding initiation | 70S-scanning initiation I t is textbook knowledge that 30S subunits initiate protein synthesis in bacteria; they recognize the initiation site of the mRNA composed of the Shine-Dalgarno (SD) sequence, the AUG codon, and fMet-tRNA, together with three initiation factors (IFs) forming the 30S initiation complex (30SIC). Association of the large 50S subunit triggers the release of the IFs, leading to the 70S initiation complex (70SIC) that enters the elongation phase of translation (reviewed in 1). We term this initiation path the "30S-binding mode" of bacterial initiation. After elongation and termination, it is thought that the ribosome dissociates into its subunits, thus providing 30S subunits for the next round of initiation.The functional role of IF2 is well defined. It can bind directly to the 30S, providing a docking site for fMet-tRNA (2), but it can also enter the 30S subunit as ternary complex fMet-tRNA•IF2•GTP (3). Both IF2 and IF3 are essential for viability. IF3 has a binding site at the 30S interface (4), which explains its antiassociation effect (5, 6), as well as its role in dissociation of the terminating 70S ribosome (7). However, the in vivo concentration of IF3 is 100-fold less (8) than required for full dissociation of 70S in vitro (4). Evidence for the presence of IF3 on 70S ribosomes was reported (9), indicating that the functional spectrum of IF3 is possibly not restricted to an antiassociation effect. Both IF3 and IF2 are also responsible for the fidelity of decoding the initiation AUG by fMet-tRNA Met f at the P site of 30S subun...

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Evolutionary and genetic analyses of mitochondrial translation initiation factors identify the missing mitochondrial IF3 in S. cerevisiae

Cited by 40 publications

References 91 publications

Mitochondrial translation initiation machinery: Conservation and diversification

Mitochondrial translation initiation machinery: Conservation and diversification

Mitochondrial ribosomes in cancer

70S-scanning initiation is a novel and frequent initiation mode of ribosomal translation in bacteria

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