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Removal of an Internal Translational Start Site from mRNA While Retaining Expression of the Full-Length Protein
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CUG start codon generates thioredoxin/glutathione reductase isoforms in mouse testes
Maxim V Gerashchenko1, Dan Su, Vadim N Gladyshev
1Department of Biochemistry and Redox Biology Center, University of Nebraska, Lincoln, Nebraska 68588, USA.
The Journal of Biological Chemistry
|December 19, 2009
Summary
Mammalian thioredoxin/glutathione reductase (TGR) genes use non-canonical CUG start codons, not AUG, to initiate translation. This inefficient initiation generates two TGR protein isoforms in mice, with implications for enzyme function.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Mammalian thioredoxin reductases are crucial selenocysteine-containing enzymes.
- Thioredoxin/glutathione reductase (TGR) is a related enzyme with a unique glutaredoxin domain, highly expressed in testes.
Purpose of the Study:
- To investigate the translation initiation mechanism of mammalian thioredoxin/glutathione reductase (TGR).
- To identify the actual start codon and understand the generation of TGR protein isoforms.
Main Methods:
- Bioinformatic analysis of TGR genes.
- Immunoblot assays and proteomic analyses.
- Gene engineering and expression studies in cultured cells and mouse testes.
Main Results:
- Human and other mammalian TGR genes lack canonical AUG start codons.
- A CUG codon, upstream of previously assumed start sites, functions as the true start codon in mouse TGR.
- CUG acts as an inefficient start codon, leading to the production of two TGR isoforms.
- A novel, longer TGR isoform is cytosolic and found in mouse spermatids.
Conclusions:
- The CUG codon is utilized as an inefficient start codon in mammalian TGR evolution, generating protein isoforms.
- This mechanism allows for alternative translation initiation, producing distinct TGR forms with potential functional differences.
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