Sequence-Specific RNA Binding by a Nova KH Domain: Implications for Paraneoplastic Disease and the Fragile X Syndrome

The structure of a Nova protein K homology (KH) domain recognizing single-stranded RNA has been determined at 2.4 Å resolution. Mammalian Nova antigens (1 and 2) constitute an important family of regulators of RNA metabolism in neurons, first identified using sera from cancer patients with the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia (POMA). The structure of the third KH domain (KH3) of Nova-2 bound to a stem loop RNA resembles a molecular vise, with 5′-Ura-Cyt-Ade-Cyt-3′ pinioned between an invariant Gly-X-X-Gly motif and the variable loop. Tetranucleotide recognition is supported by an aliphatic α helix/β sheet RNA-binding platform, which mimics 5′-Ura-Gua-3′ by making Watson-Crick-like hydrogen bonds with 5′-Cyt-Ade-3′. Sequence conservation suggests that fragile X mental retardation results from perturbation of RNA binding by the FMR1 protein.