Initiation of Protein Synthesis in Mammalian Cells with Codons Other Than AUG and Amino Acids Other Than Methionine

Drabkin, Harold J.; RajBhandary, Uttam L.

doi:10.1128/mcb.18.9.5140

Cited by 84 publications

(64 citation statements)

References 59 publications

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“…The differential expression rates of ACC1 and HFA1 with the latter being extremely low may be due to this fact. Although eucaryotes and, in particular, yeast almost exclusively use AUG as an initiation codon, systematic studies with mutationally altered AUGs revealed that a series of alternative codons may initiate mammalian translation in vivo and in vitro (32,33). Also in yeast, codons other than AUG were effective when combined with either appropriately mutated initiator tRNAs or initiation factors (32,34).…”

Section: Discussionmentioning

confidence: 99%

“…In particular with non-AUG initiation codons, specific nucleotides in the surrounding RNA context appear to be important determinants of initiation efficiency (35)(36)(37). In fact, some of the alternative initiation triplets identified in mammalian systems such as ACG, AUU, or AUA (33) are present within the HFA1 leader. It remains to be shown whether one of them acts, possibly together with an appropriate sequence context, as the in vivo initiation site of Hfa1p translation.…”

Section: Discussionmentioning

confidence: 99%

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HFA1 Encoding an Organelle-specific Acetyl-CoA Carboxylase Controls Mitochondrial Fatty Acid Synthesis in Saccharomyces cerevisiae

Hoja

Marthol

Hofmann

et al. 2004

Journal of Biological Chemistry

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The Saccharomyces cerevisiae gene, HFA1, encodes a >250-kDa protein, which is required for mitochondrial function. Hfa1p exhibits 72% overall sequence similarity (54% identity) to ACC1-encoded yeast cytoplasmic acetyl-CoA carboxylase. Nevertheless, HFA1 and ACC1 functions are not overlapping because mutants of the two genes have different phenotypes and do not complement each other. Whereas ACC1 is involved in cytoplasmic fatty acid synthesis, the phenotype of hfa1⌬ disruptants resembles that of mitochondrial fatty-acid synthase mutants. They fail to grow on lactate or glycerol, and the mitochondrial cofactor, lipoic acid, is reduced to <10% of its normal cellular concentration. Other than Acc1p, the N-terminal sequence of Hfa1p comprises a canonical mitochondrial targeting signal together with a matrix protease cleavage site. Accordingly, the HFA1-encoded protein was specifically assigned by Western blotting of appropriate cell fractions to the mitochondrial compartment. Removal of the mitochondrial targeting sequence abolished the competence of HFA1 DNA to complement hfal null mutants. Conversely and in contrast to the intact HFA1 sequence, the signal sequence-free HFA1 gene complemented the mutational loss of cytoplasmic acetyl-CoA carboxylase. Expression of HFA1 under the control of the ACC1 promoter restored cellular ACC activity in ACC1-defective yeast mutants to wild type levels. From this finding, it is concluded that HFA1 encodes a specific mitochondrial acetyl-CoA carboxylase providing malonyl-CoA for intraorganellar fatty acid and, in particular, lipoic acid synthesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HFA1 Encoding an Organelle-specific Acetyl-CoA Carboxylase Controls Mitochondrial Fatty Acid Synthesis in Saccharomyces cerevisiae

Hoja

Marthol

Hofmann

et al. 2004

Journal of Biological Chemistry

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“…However, there has been growing recognition of the use of alternate initiation codons in mammalian cells, often producing proteins with very different functions [39][40][41], as well as recognition of new mechanisms of translational control of protein structure and function [42,43]. Initiator codon mutations are uncommon, but typically they are associated with null alleles as no functional protein is produced [44][45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Ankyrin‐linked hereditary spherocytosis in an African–American kindred

et al. 2008

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Mutations of ankyrin-1 are the most frequent cause of the inherited hemolytic anemia, hereditary spherocytosis (HS), in people of European ancestry. Ankyrin-1, which provides the primary linkage between the erythrocyte membrane skeleton and the plasma membrane, has numerous isoforms generated by alternative splicing, alternate polyadenylation, use of tissue-specific promoters, and alternate NH 2 or COOH-termini. Mutation detection in erythrocyte membrane protein genes, including ankyrin, has been a challenge, primarily due to the large size of these genes, and the apparent frequent occurrence of HS-associated null alleles. Using denaturing high-performance liquid chromatography (DHPLC), we screened the ankyrin gene of the proband of a large, three generation African-American kindred with ankyrin-deficient HS. DHPLC yielded an abnormal chromatogram for exon 1. Examination of the corresponding exon 1 sequence in genomic DNA from the proband revealed heterozygosity for a mutation of the initiator methionine (ATG to ATA Met 1 Ile). Coupled in vitro transcription/translation studies with rabbit reticulocyte lysates demonstrated that the wild-type ankyrin erythroid cDNA initiates only from the known initiator methionine, indicating that the use of alternate initiator methionine is not a mechanism of isoform diversity in erythroid cells. The mutant ankyrin allele, unlike some initiator methionine mutations that utilize downstream codons for translation initiation, was associated with a null allele. This is the first report describing ankyrin-linked HS in an African-American kindred. Am. J. Hematol. 83:789-794, 2008. V

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“…In contrast, two reports suggest that non-AUG codons are initiated with another amino acid than methionine. Using mutant tRNAs, it was shown that GUC and CAG can initiate protein synthesis in COS1 cells, respectively, with valine or glutamine (Drabkin and RajBhandary, 1998). It is therefore demonstrated, although in a manipulated situation, that initiation can occur in the absence of Met tRNA.…”

Section: Is Thementioning

confidence: 99%

Generation of protein isoform diversity by alternative initiation of translation at non‐AUG codons

Touriol

Bornes

Bonnal

et al. 2003

Biology of the Cell

229

198

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The use of several translation initiation codons in a single mRNA, by expressing several proteins from a single gene, contributes to the generation of protein diversity. A small, yet growing, number of mammalian mRNAs initiate translation from a non-AUG codon, in addition to initiating at a downstream in-frame AUG codon. Translation initiation on such mRNAs results in the synthesis of proteins harbouring different amino terminal domains potentially conferring on these isoforms distinct functions. Use of non-AUG codons appears to be governed by several features, including the sequence context and the secondary structure surrounding the codon. Selection of the downstream initiation codon can occur by leaky scanning of the 43S ribosomal subunit, internal entry of ribosome or ribosomal shunting. The biological significance of non-AUG alternative initiation is demonstrated by the different subcellular localisations and/or distinct biological functions of the isoforms translated from the single mRNA as illustrated by the two main angiogenic factor genes encoding the fibroblast growth factor 2 (FGF2) and the vascular endothelial growth factor (VEGF). Consequently, the regulation of alternative initiation of translation might have a crucial role for the biological function of the gene product.

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Initiation of Protein Synthesis in Mammalian Cells with Codons Other Than AUG and Amino Acids Other Than Methionine

Cited by 84 publications

References 59 publications

HFA1 Encoding an Organelle-specific Acetyl-CoA Carboxylase Controls Mitochondrial Fatty Acid Synthesis in Saccharomyces cerevisiae

HFA1 Encoding an Organelle-specific Acetyl-CoA Carboxylase Controls Mitochondrial Fatty Acid Synthesis in Saccharomyces cerevisiae

Ankyrin‐linked hereditary spherocytosis in an African–American kindred

Generation of protein isoform diversity by alternative initiation of translation at non‐AUG codons

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