Abstract
Selenium is a trace element with significant biomedical potential. It is essential in mammals due to its occurrence in several proteins in the form of selenocysteine (Sec). One of the most abundant mammalian Sec-containing proteins is selenoprotein W (SelW). This protein of unknown function has a broad expression pattern and contains a candidate CXXU (where U represents Sec) redox motif. Here, we report the solution structure of the Sec13-->Cys variant of mouse SelW determined through high resolution NMR spectroscopy. The protein has a thioredoxin-like fold with the CXXU motif located in an exposed loop similarly to the redox-active site in thioredoxin. Protein dynamics studies revealed the rigidity of the protein backbone and mobility of two external loops and suggested a role of these loops in interaction with SelW partners. Molecular modeling of structures of other members of the Rdx family based on the SelW structure identified new conserved features in these proteins, including an aromatic cluster and interacting loops. Our previous study suggested an interaction between SelW and 14-3-3 proteins. In the present work, with the aid of NMR spectroscopy, we demonstrated specificity of this interaction and identified mobile loops in SelW as interacting surfaces. This finding suggests that 14-3-3 are redox-regulated proteins.
Highlights
Many cellular processes are known to be regulated through reduction and oxidation [1]
By utilizing affinity columns containing mutant versions of Rdx proteins, we found that selenoprotein W (SelW) binds 14-3-3 proteins, whereas Rdx12 binds glutathione peroxidase 1 [9]
In conclusion, this study reports the first solution structure of mammalian SelW that was calculated through high resolution NMR spectroscopy
Summary
Many cellular processes are known to be regulated through reduction and oxidation (redox) [1] This regulation is carried out by a set of designated proteins, oxidoreductases. In addition to oxidoreductases containing catalytic redoxactive thiols, some enzymes evolved that possess an active site selenocysteine (Sec)2 [5]. Several selenoproteins have recently been functionally characterized and found to be oxidoreductases [8] Both major cellular redox systems, the thioredoxin and glutathione systems, are dependent on selenoproteins (thioredoxin reductases and glutathione peroxidases, respectively). We recently reported on a family of selenoproteins and their Cys homologs, designated as the Rdx family [9] Mammalian members of this family include selenoproteins SelW, SelT, SelH, SelV, and a Cys-containing Rdx protein. The SelW/14-3-3 interaction differs from that observed for other 14-3-3 partners, since SelW does not have canonical 14-3-3 binding motifs (R(S/X)XpSXP or RXXXpSXP, where X denotes any amino acid residue, and pS represents a phospho-
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