title: Alternative splicing involving the thioredoxin reductase module in mammals: a glutaredoxin-containing thioredoxin reductase 1.
abstract: Thioredoxin reductase 1 (TR1) is a key component in the thioredoxin system, one of major redox systems in mammals that links NADPH and thiol-dependent processes. Mammalian TR1 genes are known to be regulated by alternative splicing. In this report, comparative genomic analyses were used to identify and characterize species-specific and common alternative forms of mammalian TR1 genes. Six human TR1 isoforms were identified that were derived from a large number of transcripts and differed in their N-terminal sequences. One isoform resulted from exons located 30-70 kb upstream of the previously identified core TR1 promoter and was composed of a basic TR1 module fused to a glutaredoxin (Grx) domain that contained an unusual active site CTRC sequence. This TR1 form occurred in humans, dogs, and chimpanzees but was inactivated in mice and rats. The CTRC motif in the human enzyme made the N-terminal domain inactive in the Grx assays tested. However, when mutated to CPYC, an active site present in most Grxs, the Grx domain was active. In addition, the presence of the Grx domain interfered with the TR1 activity, distinguishing this enzyme from other proteins with Grx and TR fusions. The data suggest that the fusion of the basic TR1 module and variable N-terminal sequences links the pyridine nucleotide thiol/disulfide oxidoreductase pathway to specific cellular redox functions and may control spatial and temporal expression of TR1 transcripts. Our data also suggest that various N-terminal extensions in mammalian TRs are often expressed in testes.
authors.affiliation: Department of Biochemistry, University of Nebraska--Lincoln, Lincoln, Nebraska 68588, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Su
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D015870:Gene Expression; D015894:Genome, Human; D054477:Glutaredoxins; D006801:Humans; D007700:Kinetics; D008297:Male; D008322:Mammals / Q000235:genetics; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D010802:Phylogeny; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013737:Testis / Q000378:metabolism; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: C516005:GLRX protein, human; D054477:Glutaredoxins; D020033:Protein Isoforms; D010088:Oxidoreductases; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D013880:Thioredoxin-Disulfide Reductase