Divergence of Function in the Thioredoxin Fold Suprafamily:  Evidence for Evolution of Peroxiredoxins from a Thioredoxin-like Ancestor

Copley, Shelley D.; Novak, Walter R. P.; Babbitt, Patricia C.

doi:10.1021/bi048947r

Cited by 144 publications

(133 citation statements)

References 53 publications

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“…As expected, the structure of XfPrxQ C47S includes a canonical Trx fold (20) with insertions and extensions that form a five-stranded mixed ␤-sheet (in the order ␤31-␤41-␤51-␤82-␤91) surrounded by six ␣-helices and four additional ␤-strands in the ␣1-␤1-␤2-␣2-␤3-␣3-␤4-␣4-␤5-␣5-␤6-␤7-␤8-␤9-␣6 arrangement of secondary structure elements. According to structural comparisons with known Prx structures and based on the classification suggested by Copley et al (17), we confirmed that XfPrxQ is a class 1 Prx (Table 1).…”

Section: Resultssupporting

confidence: 78%

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Structural and Biochemical Characterization of Peroxiredoxin Qβ from Xylella fastidiosa

Horta

Oliveira

Discola

et al. 2010

Journal of Biological Chemistry

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The phytopathogenic bacterium Xylella fastidiosa is the etiological agent of various plant diseases. To survive under oxidative stress imposed by the host, microorganisms express antioxidant proteins, including cysteine-based peroxidases named peroxiredoxins. This work is a comprehensive analysis of the catalysis performed by PrxQ from X. fastidiosa (XfPrxQ) that belongs to a peroxiredoxin class still poorly characterized and previously considered as moderately reactive toward hydroperoxides. Contrary to these assumptions, our competitive kinetics studies have shown that the second-order rate constants of the peroxidase reactions of XfPrxQ with hydrogen peroxide and peroxynitrite are in the order of 10 7 and 10 6 M ؊1 s ؊1 , respectively, which are as fast as the most efficient peroxidases. The XfPrxQ disulfides were only slightly reducible by dithiothreitol; therefore, the identification of a thioredoxin system as the probable biological reductant of XfPrxQ was a relevant finding. We also showed by site-specific mutagenesis and mass spectrometry that an intramolecular disulfide bond between Cys-47 and Cys-83 is generated during the catalytic cycle. Furthermore, we elucidated the crystal structure of XfPrxQ C47S in which Ser-47 and Cys-83 lie ϳ12.3 Å apart. Therefore, significant conformational changes are required for disulfide bond formation. In fact, circular dichroism data indicated that there was a significant redox-dependent unfolding of ␣-helices, which is probably triggered by the peroxidatic cysteine oxidation. Finally, we proposed a model that takes data from this work as well data as from the literature into account.

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Section: Resultssupporting

confidence: 78%

“…Later on, another classification based on both amino acid sequence and structural similarities was proposed and provided insights on the evolution of proteins within the Trx superfamily, which includes Prxs (17). Among the four Prx classes, class 1 is the most ancestral from which the other three classes arose.…”

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confidence: 99%

Structural and Biochemical Characterization of Peroxiredoxin Qβ from Xylella fastidiosa

Horta

Oliveira

Discola

et al. 2010

Journal of Biological Chemistry

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“…First, all three proteins contain an interacting residue on a b strand directly behind the cysteine: Ser 72 of 1prx, Cys 72 of 1hd2, and His 176 of 1j0x. Second, residue Tyr 317 in 1j0x is located near the cysteine in a similar manner as Arg 132 in 1prx and Arg 127 in 1hd2, a residue thought to be important in stabilizing the deprotonated cysteine in these Prxs (Wood et al 2003b;Copley et al 2004). These observations suggest that these common features might play similar roles in cysteine deprotonation in these proteins.…”

Section: Comparison Of Functional Site Profiling and Electrostatic Anmentioning

confidence: 99%

Functional site profiling and electrostatic analysis of cysteines modifiable to cysteine sulfenic acid

et al. 2008

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Cysteine sulfenic acid (Cys-SOH), a reversible modification, is a catalytic intermediate at enzyme active sites, a sensor for oxidative stress, a regulator of some transcription factors, and a redox-signaling intermediate. This post-translational modification is not random: specific features near the cysteine control its reactivity. To identify features responsible for the propensity of cysteines to be modified to sulfenic acid, a list of 47 proteins (containing 49 known Cys-SOH sites) was compiled. Modifiable cysteines are found in proteins from most structural classes and many functional classes, but have no propensity for any one type of protein secondary structure. To identify features affecting cysteine reactivity, these sites were analyzed using both functional site profiling and electrostatic analysis. Overall, the solvent exposure of modifiable cysteines is not different from the average cysteine. The combined sequence, structure, and electrostatic approaches reveal mechanistic determinants not obvious from overall sequence comparison, including: (1) pK a s of some modifiable cysteines are affected by backbone features only; (2) charged residues are underrepresented in the structure near modifiable sites; (3) threonine and other polar residues can exert a large influence on the cysteine pK a ; and (4) hydrogen bonding patterns are suggested to be important. This compilation of Cys-SOH modification sites and their features provides a quantitative assessment of previous observations and a basis for further analysis and prediction of these sites. Agreement with known experimental data indicates the utility of this combined approach for identifying mechanistic determinants at protein functional sites.Keywords: functional site profile; redox signaling; cysteine sulfenic acid; cysteine reactivity; mechanistic determinants; post-translational modification; oxidative modification Supplemental material: see www.proteinscience.org Protein post-translational modifications are well known to play important biological roles by rapidly modifying the structure and function of proteins. The most common and well-known example is the involvement of protein phosphorylation in signal transduction. Analysis of phosphorylation sites has led to a better understanding of kinase substrate specificity (Brinkworth et al. 2002;Kobe et al. 2005), methods for site prediction (Koenig and Grabe 2004;Huang et al. 2005;Plewczynski et al. 2005;Xue et al. 2005), and a combined experimental/computational approach that has led to a better understanding of the yeast phosphoproteome (Brinkworth et al. 2006;Molina et al. 2007).The reversible oxidation of cysteine side chains to cysteine sulfenic acid (Cys-SOH) has been recognized as Reprint requests to: Jacquelyn S. Fetrow, 100 Olin Physical Laboratory, 7507 Reynolda Station, Wake Forest University, Winston-Salem, NC 27019-7507, USA; e-mail: fetrowjs@wfu.edu; fax: (336) 758-6142.Abbreviations: Prx, peroxiredoxin; Msr, methionine sulfoxide reductase; Cys-SOH, cysteine sulfenic acid; GAPDH...

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“…Sequence analysis suggested that it belongs to the thioredoxin-like protein superfamily (22). Homology modeling showed that YkuV together with YbdE are structurally similar to the cytochrome maturation proteins (CMPs), such as the recently discovered ResA from B. subtilis (23).…”

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confidence: 99%

The Bacillus subtilis YkuV Is a Thiol:Disulfide Oxidoreductase Revealed by Its Redox Structures and Activity

Zhang

Hu²,

Guo³

et al. 2006

Journal of Biological Chemistry

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The Bacillus subtilis YkuV responds to environmental oxidative stress and plays an important role for the bacteria to adapt to the environment. Bioinformatic analysis suggests that YkuV is a homolog of membrane-anchored proteins and belongs to the thioredoxin-like protein superfamily containing the typical Cys-Xaa-XaaCys active motif. However, the biological function of this protein remains unknown thus far. In order to elucidate the biological function, we have determined the solution structures of both the oxidized and reduced forms of B. subtilis YkuV by NMR spectroscopy and performed biochemical studies. Our results demonstrated that the reduced YkuV has a low midpoint redox potential, allowing it to reduce a variety of protein substrates. The overall structures of both oxidized and reduced forms are similar, with a typical thioredoxinlike fold. However, significant conformational changes in the CysXaa-Xaa-Cys active motif of the tertiary structures are observed between the two forms. In addition, the backbone dynamics provide further insights in understanding the strong redox potential of the reduced YkuV. Furthermore, we demonstrated that YkuV is able to reduce different protein substrates in vitro. Together, our results clearly established that YkuV may function as a general thiol:disulfide oxidoreductase, which acts as an alternative for thioredoxin or thioredoxin reductase to maintain the reducing environment in the cell cytoplasm.Thioredoxins are small proteins (ϳ12 kDa) that are ubiquitously present in all kinds of life forms from archaebacteria to human (1). Generally, they function as protein thiol:disulfide oxidoreductases for maintaining the reducing environment in cytoplasm, protecting cells against hydrogen peroxide (2) and oxidative stress (3). In addition to the general function as a thiol:disulfide oxidoreductase, some thioredoxins from different organisms are also involved in various specified biological processes and therefore have specific biological functions. For example, thioredoxin is an essential subunit of bacteriophage T7 DNA polymerase in Escherichia coli (4), and in eukaryotes, thioredoxins facilitate the refolding of disulfide-containing proteins (5) and modulate the activity of certain transcription factors (6, 7). Moreover, thioredoxins have been considered as a possible target for drug development because of their roles in stimulating cancer cell growth and as an inhibitor of apoptosis (8).The thioredoxin fold was first characterized from E. coli thioredoxin, which consists of a central five-stranded mixed ␤-sheet surrounded by four ␣-helices (9 -11). Subsequently, the structures of several thioredoxins from different species were determined (11-16). Notably, from E. coli to human, thioredoxins all share the same thioredoxin fold with the Cys-Gly-Pro-Cys active motif. In addition to thioredoxins, a large number of proteins comprising the basic thioredoxin fold with the CysXaa-Xaa-Cys active motif in the active site have been characterized as thioredoxin-like proteins, which co...

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Divergence of Function in the Thioredoxin Fold Suprafamily: Evidence for Evolution of Peroxiredoxins from a Thioredoxin-like Ancestor

Cited by 144 publications

References 53 publications

Structural and Biochemical Characterization of Peroxiredoxin Qβ from Xylella fastidiosa

Structural and Biochemical Characterization of Peroxiredoxin Qβ from Xylella fastidiosa

Functional site profiling and electrostatic analysis of cysteines modifiable to cysteine sulfenic acid

The Bacillus subtilis YkuV Is a Thiol:Disulfide Oxidoreductase Revealed by Its Redox Structures and Activity

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