Selenocysteine (Sec, U) insertion into proteins is directed by translational 
recoding of specific UGA codons located upstream of a stem-loop structure known 
as Sec insertion sequence (SECIS) element. Selenoproteins with known functions 
are oxidoreductases containing a single redox-active Sec in their active sites. 
In this work, we identified a family of selenoproteins, designated SelL, 
containing two Sec separated by two other residues to form a UxxU motif. SelL 
proteins show an unusual occurrence, being present in diverse aquatic organisms, 
including fish, invertebrates, and marine bacteria. Both eukaryotic and 
bacterial SelL genes use single SECIS elements for insertion of two Sec. In 
eukaryotes, the SECIS is located in the 3' UTR, whereas the bacterial SelL SECIS 
is within a coding region and positioned at a distance that supports the 
insertion of either of the two Sec or both of these residues. SelL proteins 
possess a thioredoxin-like fold wherein the UxxU motif corresponds to the 
catalytic CxxC motif in thioredoxins, suggesting a redox function of SelL 
proteins. Distantly related SelL-like proteins were also identified in a variety 
of organisms that had either one or both Sec replaced with Cys. Danio rerio 
SelL, transiently expressed in mammalian cells, incorporated two Sec and 
localized to the cytosol. In these cells, it occurred in an oxidized form and 
was not reducible by DTT. In a bacterial expression system, we directly 
demonstrated the formation of a diselenide bond between the two Sec, 
establishing it as the first diselenide bond found in a natural protein.