The expression of selenoproteins requires the translational recoding of the UGA 
stop codon to selenocysteine. In eukaryotes, this requires an RNA stem loop 
structure in the 3'-untranslated region, termed a selenocysteine insertion 
sequence (SECIS), and SECIS-binding protein 2 (SBP2). This study implicates SBP2 
in dictating the hierarchy of selenoprotein expression, because it is the first 
to show that SBP2 distinguishes between SECIS elements in vitro. Using RNA 
electrophoretic mobility shift assays, we demonstrate that a naturally occurring 
mutation in SBP2, which correlates with abnormal thyroid hormone function in 
humans, lies within a novel, bipartite RNA-binding domain. This mutation alters 
the RNA binding affinity of SBP2 such that it no longer stably interacts with a 
subset of SECIS elements. Assays performed under competitive conditions to mimic 
intracellular conditions suggest that the differential affinity of SBP2 for 
various SECIS elements will determine the expression pattern of the 
selenoproteome. We hypothesize that the selective loss of a subset of 
selenoproteins, including some involved in thyroid hormone homeostasis, is 
responsible for the abnormal thyroid hormone metabolism previously observed in 
the affected individuals.