The intrinsically disordered membrane protein selenoprotein S is a reductase in vitro

Significance Statement

To further investigate the unique role of selenocysteine, we compared the wild type selenoprotein S to the cysteine-containing mutant. The reduction potential of selenoprotein S was determined to be − 234 mV. While this value is consistent with selenoprotein S being a partner of thioredoxin, it does not stand out as particularly low as had been predicted for selenoproteins. The redox potential of the cysteine-mutant is only 23 mV higher than that of the wild type. Only the selenocysteine-containing enzyme is active. One distinct advantage that the selenocysteine-containing SelS has is that it is highly resistant to damage by hydrogen peroxide. Thus, the presence of selenocysteine allows selenoprotein S to both detect the presence of ROS and evade inactivation by them. selenoprotein S is a member of a large eukaryotic membrane protein family that is intrinsically disordered. It is an ER-residing single-span transmembrane protein with an intrinsically disordered C-terminal domain. While many intrinsically disordered proteins require a protein partner to perform their function, clearly selenoprotein S is an efficient reductase even in the absence of a protein partner. It is possible that other members of this family can be similarly enzymatically active in redox pathways, even in the absence of their protein partners.


intrinsically disordered membrane protein selenoprotein S is reductase in vitro- Global Medical Discovery







Liu J, Li F, Rozovsky S.

Biochemistry. 2013 May 7;52(18):3051-61.

Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA.


Selenoprotein S (SelS or VIMP) is an intrinsically disordered membrane enzyme that provides protection against reactive oxidative species. selenoprotein S is a member of the endoplasmic reticulum-associated protein  degradation pathway, but its precise enzymatic function is unknown. Because it contains the rare amino acid selenocysteine, it belongs to the family of selenoproteins, which are typically oxidoreductases. Its exact enzymatic function is key to understanding how the cell regulates the response to oxidative stress and thus influences human health and aging. To identify its enzymatic function, we have isolated the selenocysteine-containing enzyme by relying on the aggregation of forms that do not have this reactive residue. That allows us to establish that SelS is primarily a thioredoxin-dependent reductase. It is capable of reducing hydrogen peroxide but is not an efficient or broad-spectrum peroxidase. Only the selenocysteine-containing enzyme is active. In addition, the reduction potential of selenoprotein S was determined to be -234 mV using electrospray ionization mass spectrometry. This value is consistent with SelS being a partner of thioredoxin. On the basis of this information, selenoprotein S can directly combat reactive oxygen species but is also likely to participate in a signaling pathway, via a yet unidentified substrate.

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