Selenocysteine (Sec), the 21st amino acid in protein, is encoded by UGA. The Sec 
insertion sequence (SECIS) element, which is the stem-loop structure present in 
3' untranslated regions (UTRs) of eukaryotic selenoprotein-encoding genes, is 
essential for recognition of UGA as a codon for Sec rather than as a stop 
signal. We now report the identification of a new eukaryotic selenoprotein, 
designated selenoprotein M (SelM). The 3-kb human SelM-encoding gene has five 
exons and is located on chromosome 22 but has not been correctly identified by 
either Celera or the public Human Genome Project. We characterized human and 
mouse SelM cDNA sequences and expressed the selenoprotein in various mammalian 
cell lines. The 3" UTR of the human, mouse, and rat SelM-encoding genes lacks a 
canonical SECIS element. Instead, Sec is incorporated in response to a conserved 
mRNA structure, in which cytidines are present in place of the adenosines 
previously considered invariant. Substitution of adenosines for cytidines did 
not alter Sec incorporation; however, other mutant structures did not support 
selenoprotein synthesis, demonstrating that this new form of SECIS element is 
functional. SelM is expressed in a variety of tissues, with increased levels in 
the brain. It is localized to the perinuclear structures, and its N-terminal 
signal peptide is necessary for protein translocation.