The tetranucleotide UCAY directs the specific recognition of RNA by the Nova K-homology 3 domain

The Nova family of proteins are target antigens in the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia and contain K-homology (KH)-type RNA binding domains. The Nova-1 protein has recently been shown to regulat e alternative splicing of the alpha 2 glycine receptor subunit pre-mRNA by binding to an intronic element containing repeats of the tetranucleotide UC AU, Here, we have used selection-amplification to demonstrate that the KH3 domain of Nova recognizes a single UCAY element in the context of a 20-base hairpin RNA; the UCAY tetranucleotide is optimally presented as a loop ele ment of the hairpin scaffold and requires protein residues C-terminal to th e previously defined KH domain. These results suggest that KH domains in ge neral recognize tetranucleotide motifs and that biological RNA targets of K H domains may use either RNA secondary structure or repeated sequence eleme nts to achieve high affinity and specificity of protein binding.