The Refined Structure of the Selenoenzyme Glutathione Peroxidase at 0.2‐nm Resolution

Epp, Otto; Ladenstein, Rudolf; Wendel, Albrecht

doi:10.1111/j.1432-1033.1983.tb07429.x

Cited by 657 publications

(480 citation statements)

References 39 publications

(28 reference statements)

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“…4). This loop does not originate from the thioredoxin domain, but the ␤3/␣3 turn is also exploited in other thioredoxin-related proteins for non-related inserts of varying size and structure (14,15). In these proteins it has been suggested that the insertion may play a role in substrate binding (14).…”

Section: Most Wind Mutants Display Normal Expression and Dimerizationmentioning

confidence: 99%

Mapping of a Substrate Binding Site in the Protein Disulfide Isomerase-related Chaperone Wind Based on Protein Function and Crystal Structure

Barnewitz

Guo

Sevvana

et al. 2004

Journal of Biological Chemistry

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The protein disulfide isomerase (PDI)-related protein Wind is essential inPDI 1 -related proteins are residents of the lumen of the endoplasmic reticulum (ER) with various functions, including redox and chaperone activities, regulation of calcium homeostasis, and regulation of protein export from the ER for degradation. These functions are essential for maintaining a productive folding environment for many secretory proteins within the ER (1, 2) that may be critical for viability of the organism (3, 4). The chaperone function of these proteins, and probably to varying extents redox activity as well, relies on their ability to interact non-covalently with specific peptide sequences or epitopes in substrate proteins (2). However, until recently no concise data on peptide specificity, peptide binding sites, or the molecular basis for the observed substrate selectivity of these proteins were available. Data on such inherently weak interactions would require detailed knowledge of the three-dimensional structure of the protein concerned. Although independent NMR structures of the isolated a-and b-type thioredoxin fold domains (redox-active and redox-inactive domains, respectively) of PDI have been reported (5, 6), no complete structure of a eukaryotic PDI protein was available. Most PDI proteins are redox-active, and the involvement of relatively strong heteromeric disulfide bond formation and reduction in assays aimed at elucidating the nature of weak chaperone interactions poses further problems. Because the bЈ-domain has been identified as the major substrate binding site in PDI (7), much attention has been focused on these redox-inactive domains. However, the lack of suitable substrates of physiological relevance with a maturation process that can be readily monitored has complicated these studies. Thus much could be learned from the study of peptide binding and chaperone activity of a naturally occurring PDI family protein lacking redox properties but having a clearly defined substrate that can be studied both in vivo and in vitro.We recently described the first crystal structure of a complete PDI-related protein of the eukaryotic ER (3). This protein, Wind, is essential in Drosophila melanogaster for dorsal-ventral patterning within the developing embryo, and it is required for ER export of an essential Golgi transmembrane proteoglycan modifying enzyme, Pipe (a 2-O-sulfotransferase) (8). Apart from a b-domain, Wind also has a unique C-terminal domain found only in the PDI-D subclass of PDI-related proteins (1). The function of the D-domain is poorly understood, although in Dictyostelium discoideum PDI-D it was shown to play a role in ER retention (9). Recently, we have shown that the Pipe-processing activity requires both the b-and D-domains of Wind. Although the mammalian Wind orthologue ERp28/29 cannot replace Wind in Pipe processing, the D-domains of both proteins could be exchanged, indicating functional conservation between the proteins (3).Here, we show that Wind binds Pipe directly in vitro, and we map a ...

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Section: Most Wind Mutants Display Normal Expression and Dimerizationmentioning

confidence: 99%

Mapping of a Substrate Binding Site in the Protein Disulfide Isomerase-related Chaperone Wind Based on Protein Function and Crystal Structure

Barnewitz

Guo

Sevvana

et al. 2004

Journal of Biological Chemistry

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“…Structural models of GPx4 have been generated (Aumann et al, 1997;Mauri et al, 2003) based on the X-ray coordinates of other GPx isoforms (Epp et al, 1983;Ren et al, 1997). Although the degree of amino acid conservation among GPx isoforms is rather low, these models served in the past as suitable tools to predict target amino acids for site-directed mutagenesis to impede the catalytic activity (Maiorino et al, 1995(Maiorino et al, , 1998.…”

Section: Molecular Enzymology and Structural Aspects Of Gpx4mentioning

confidence: 99%

Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function

Savaskan

Ufer

Kühn

et al. 2007

BCHM

112

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Selenoproteins have been recognized as modulators of brain function and signaling. Phospholipid hydroperoxide glutathione peroxidase (GPx4/PHGPx) is a unique member of the selenium-dependent glutathione peroxidases in mammals with a pivotal role in brain development and function. GPx4 exists as a cytosolic, mitochondrial, and nuclear isoform derived from a single gene. In mice, the GPx4 gene is located on chromosome 10 in close proximity to a functional retrotransposome that is expressed under the control of captured regulatory elements. Elucidation of crystallographic data uncovered structural peculiarities of GPx4 that provide the molecular basis for its unique enzymatic properties and substrate specificity. Monomeric GPx4 is multifunctional: it acts as a reducing enzyme of peroxidized phospholipids and thiols and as a structural protein. Transcriptional regulation of the different GPx4 isoforms requires several isoform-specific cis-regulatory sequences and trans-activating factors. Cytosolic and mitochondrial GPx4 are the major isoforms exclusively expressed by neurons in the developing brain. In stark contrast, following brain trauma, GPx4 is specifically upregulated in non-neuronal cells, i.e., reactive astrocytes. Molecular approaches to genetic modification in mice have revealed an essential and isoform-specific function for GPx4 in development and disease. Here we review recent findings on GPx4 with emphasis on its molecular structure and function and consider potential mechanisms that underlie neural development and neuropathological conditions.

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“…Selenium proved to be present in this enzyme as a selenocysteine residue (Forstrom et al, 1978, Wendel et al, 1978 that is integrated into the amino acid chain (Günzler et al, 1984). The selenocysteine residue in GPx is responsible for the catalytic efficiency, as demonstrated by site-directed mutagenesis (Rocher et al, 1992), and the X-ray analysis performed by Epp et al (1983) enabled a detailed understanding of the catalytic mechanism (Aumann et al, 1997; see also Figure 1A). …”

Section: Introduction: Some Historical Landmarksmentioning

confidence: 99%

Selenium in Biology: Facts and Medical Perspectives

Köhrl¹,

Brigelius‐Flohé²,

Böck³

et al. 2000

Biological Chemistry

245

143

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Several decades after the discovery of selenium as an essential trace element in vertebrates approximately 20 eukaryotic and more than 15 prokaryotic selenoproteins containing the 21 st proteinogenic amino acid, selenocysteine, have been identified, partially characterized or cloned from several species. Many of these proteins are involved in redox reactions with selenocysteine acting as an essential component of the catalytic cycle. Enzyme activities have been assigned to the glutathione peroxidase family, to the thioredoxin reductases, which were recently identified as selenoproteins, to the iodothyronine deiodinases, which metabolize thyroid hormones, and to the selenophosphate synthetase 2, which is involved in selenoprotein biosynthesis. Prokaryotic selenoproteins catalyze redox reactions and formation of selenoethers in (stress-induced) metabolism and energy production of E. coli, of the clostridial cluster XI and of other prokaryotes. Apart from the specific and complex biosynthesis of selenocysteine, selenium also reversibly binds to proteins, is incorporated into selenomethionine in bacteria, yeast and higher plants, or posttranslationally modifies a catalytically essential cysteine residue of CO dehydrogenase. Expression of individual eukaryotic selenoproteins exhibits high tissue specificity, depends on selenium availability, in some cases is regulated by hormones, and if impaired contributes to several pathological conditions. Disturbance of selenoprotein expression or function is associated with deficiency syndromes (Keshan and Kashin-Beck disease), might contribute to tumorigenesis and atherosclerosis, is altered in several bacterial and viral infections, and leads to infertility in male rodents.

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The Refined Structure of the Selenoenzyme Glutathione Peroxidase at 0.2‐nm Resolution

Cited by 657 publications

References 39 publications

Mapping of a Substrate Binding Site in the Protein Disulfide Isomerase-related Chaperone Wind Based on Protein Function and Crystal Structure

Mapping of a Substrate Binding Site in the Protein Disulfide Isomerase-related Chaperone Wind Based on Protein Function and Crystal Structure

Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function

Selenium in Biology: Facts and Medical Perspectives

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