title: Sequence-specific RNA binding by a Nova KH domain: implications for paraneoplastic disease and the fragile X syndrome.
abstract: The structure of a Nova protein K homology (KH) domain recognizing single-stranded RNA has been determined at 2.4 A 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 alpha helix/beta 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.
authors.affiliation: Laboratories of Molecular Biophysics, The Rockefeller University, New York, New York 10021, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Lewis
authors.forename: K
authors.initials: K
authors.lastname: Musunuru
authors.forename: K B
authors.initials: KB
authors.lastname: Jensen
authors.forename: C
authors.initials: C
authors.lastname: Edo
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: R B
authors.initials: RB
authors.lastname: Darnell
authors.forename: S K
authors.initials: SK
authors.lastname: Burley
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm; D001324:Autoantigens / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005600:Fragile X Syndrome / Q000209:etiology*; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D000090682:Neuro-Oncological Ventral Antigen; D020361:Paraneoplastic Syndromes, Nervous System / Q000209:etiology*; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000737:chemistry*; D012261:Ribonucleoproteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; C072074:HNRNPK protein, human