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-s tranded RNA has been determined at 2.4 Angstrom resolution. Mammalian Nova antigens (1 and 2) constitute an important family of regulators of RNA meta bolism in neurons, first identified using sera from cancer patients with th e autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia (POMA). Th e 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 recogni tion is supported by an aliphatic alpha helix/beta sheet RNA-binding platfo rm, which mimics 5'-Ura-Gua-3' by making Watson-Crick-like hydrogen bonds w ith 5'-Cyt-Ade-3'. Sequence conservation suggests that fragile X mental ret ardation results from perturbation of RNA binding by the FMR1 protein.