Multiple catalytically active thioredoxin folds: a winning strategy for many functions

Pedone, Emilia; Limauro, Danila; D’Ambrosio, Katia; Simone, Giuseppina De; Bartolucci, Simonetta

doi:10.1007/s00018-010-0449-9

Cited by 28 publications

(23 citation statements)

References 168 publications

(230 reference statements)

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“…Pedone et al have proposed that thermophilic protein disulfide oxidoreductase (PDO), which is a member of the thioredoxin family, plays a main role in the cytoplasmic disulfide formation in thermophilic microorganisms, such as S. solfataricus (9,10). The microorganisms possessing thermophilic PDO seem to agree with those listed by Yeates's group as the producers of abundant disul-fide-bonded proteins in the cytosol (6,7).…”

Section: Importancementioning

confidence: 94%

In Vivo Formation of the Protein Disulfide Bond That Enhances the Thermostability of Diphosphomevalonate Decarboxylase, an Intracellular Enzyme from the Hyperthermophilic Archaeon Sulfolobus solfataricus

et al. 2015

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In the present study, the crystal structure of recombinant diphosphomevalonate decarboxylase from the hyperthermophilic archaeon Sulfolobus solfataricus was solved as the first example of an archaeal and thermophile-derived diphosphomevalonate decarboxylase. The enzyme forms a homodimer, as expected for most eukaryotic and bacterial orthologs. Interestingly, the subunits of the homodimer are connected via an intersubunit disulfide bond, which presumably formed during the purification process of the recombinant enzyme expressed in Escherichia coli. When mutagenesis replaced the disulfide-forming cysteine residue with serine, however, the thermostability of the enzyme was significantly lowered. In the presence of ␤-mercaptoethanol at a concentration where the disulfide bond was completely reduced, the wild-type enzyme was less stable to heat. Moreover, Western blot analysis combined with nonreducing SDS-PAGE of the whole cells of S. solfataricus proved that the disulfide bond was predominantly formed in the cells. These results suggest that the disulfide bond is required for the cytosolic enzyme to acquire further thermostability and to exert activity at the growth temperature of S. solfataricus. IMPORTANCEThis study is the first report to describe the crystal structures of archaeal diphosphomevalonate decarboxylase, an enzyme involved in the classical mevalonate pathway. A stability-conferring intersubunit disulfide bond is a remarkable feature that is not found in eukaryotic and bacterial orthologs. The evidence that the disulfide bond also is formed in S. solfataricus cells suggests its physiological importance.

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Section: Importancementioning

confidence: 94%

In Vivo Formation of the Protein Disulfide Bond That Enhances the Thermostability of Diphosphomevalonate Decarboxylase, an Intracellular Enzyme from the Hyperthermophilic Archaeon Sulfolobus solfataricus

et al. 2015

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“…3C) and that they indeed feature the two characteristics of the Prx family. An additional helix in the variable Trx-fold insertion, αD in the Dio-insertion, is present in Prx but also in some other Trx-fold protein families (6). The N-terminal βN1/2-Θ1 module found in Dio3 cat (Fig.…”

Section: Comparison Of Dio3mentioning

confidence: 98%

“…The deiodinase crystal structure now suggests an answer to this question. The Trx superfamily comprises protein families with different functions, characterized by family-specific modifications to the Trx fold (6).…”

mentioning

confidence: 99%

Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism

Schweizer

Schlicker

Braun

et al. 2014

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

161

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Local levels of active thyroid hormone (3,3′,5-triiodothyronine) are controlled by the action of activating and inactivating iodothyronine deiodinase enzymes. Deiodinases are selenocysteine-dependent membrane proteins catalyzing the reductive elimination of iodide from iodothyronines through a poorly understood mechanism. We solved the crystal structure of the catalytic domain of mouse deiodinase 3 (Dio3), which reveals a close structural similarity to atypical 2-Cys peroxiredoxin(s) (Prx). The structure suggests a route for proton transfer to the substrate during deiodination and a Prx-related mechanism for subsequent recycling of the transiently oxidized enzyme. The proposed mechanism is supported by biochemical experiments and is consistent with the effects of mutations of conserved amino acids on Dio3 activity. Thioredoxin and glutaredoxin reduce the oxidized Dio3 at physiological concentrations, and dimerization appears to activate the enzyme by displacing an autoinhibitory loop from the iodothyronine binding site. Deiodinases apparently evolved from the ubiquitous Prx scaffold, and their structure and catalytic mechanism reconcile a plethora of partly conflicting data reported for these enzymes.hyroid hormones regulate mammalian development as well as energy expenditure and metabolism in the adult (1). The active, nuclear receptor-binding form of thyroid hormone is 3,3′,5-triiodothyronine (T 3 ). The thyroid gland mainly releases thyroxine [3,3′,5,5′-tetraiodothyronine (T 4 ); Fig. 1A], and T 3 is formed and degraded through elimination of iodine atoms from the 5′-and 5-positions, respectively (2) (Fig. S1). Three types of deiodinase enzymes are involved in activation and inactivation of thyroid hormones (Fig. S1). They form a family of transmembrane enzymes with homologous catalytic domains (2). Type II deiodinase (Dio2) catalyzes the activating (outer ring) 5′-deiodination of the prohormone T 4 to T 3 , whereas type III deiodinase (Dio3) catalyzes inactivating (inner ring) 5-deiodination (2). Type I deiodinase (Dio1) is capable of both types of reactions (3). Cells targeted by the hormone can thereby fine-tune intracellular T 3 levels through deiodinase expression according to their needs during development or upon metabolic challenges. Dio1, Dio2, and Dio3 share a conserved amino acid sequence and a selenocysteine residue essential for efficient deiodination, although nonmammalian cysteine-deiodinases have been found (4, 5). Although most of the characterized selenoproteins act as peroxidases or protein reductases, deiodinases are the only selenoenzymes known to catalyze halogen eliminations from aromatic rings. Despite a large body of experimental data, there is no coherent model for deiodinase catalysis that incorporates the bulk of available data. Results and DiscussionTo explore the unique deiodinase catalytic mechanism, we determined the crystal structure of the cytoplasmic catalytic domain of Mus musculus Dio3 (Dio3 cat ) with Sec 170 replaced by cysteine ( Fig. 1 B and C and Table 1). The structu...

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“…These proteins are generally members of the thioredoxin superfamily and include proteins such as the thioredoxins, glutaredoxins, peroxiredoxins and protein disulfi de isomerases (PDIs) [ 5 ] and also proteins associated with the function of these redox proteins [ 6 ]. Human thioredoxin-1 (Trx-1) is part of a system of proteins which include a truncated form of Trx termed Trx80, thioredoxin reductase (TrxR) and a natural inhibitory protein known as thioredoxin-interacting protein (TXNIP).…”

Section: Oxidative and Non-oxidative Actions Of Redox Proteinsmentioning

confidence: 99%

Periodontitis and Oxidative Stress: Human Studies

Nibali

Henderson

Volti

et al. 2013

Studies on Periodontal Disease

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Multiple catalytically active thioredoxin folds: a winning strategy for many functions

Cited by 28 publications

References 168 publications

In Vivo Formation of the Protein Disulfide Bond That Enhances the Thermostability of Diphosphomevalonate Decarboxylase, an Intracellular Enzyme from the Hyperthermophilic Archaeon Sulfolobus solfataricus

In Vivo Formation of the Protein Disulfide Bond That Enhances the Thermostability of Diphosphomevalonate Decarboxylase, an Intracellular Enzyme from the Hyperthermophilic Archaeon Sulfolobus solfataricus

Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism

Periodontitis and Oxidative Stress: Human Studies

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