The onconeural antigen Nova-1 is a neuron-specific RNA-binding protein, the activity of which is inhibited by paraneoplastic antibodies.
Nova-1, a protein expressed in tumors and neurons, is a target antigen in a human paraneoplastic motor disorder [paraneoplastic opsoclonus-myoclonus ataxia (POMA)]. We evaluated the relationship between the function of Nova-1 and its role as a disease antigen. We show that Nova-1 is a neuron-specific RNA-binding protein with sequence and functional similarities to FMR-1. Nova-1 mRNA is restricted to the subcortical nervous system, and the protein binds to RNA with high affinity. Nova-1 KH domains mediate this RNA binding, and point mutations within them abrogate binding. POMA disease antisera (6/6) recognize the third KH domain but not an inactive point mutant, and affinity-purified antibody blocks Nova-1 RNA binding. Thus, a cardinal feature of POMA is the production of antibodies that inhibit Nova-1-RNA interactions, suggesting such inhibition may cause the neurological disease.
Buckanovich
R J
RJ
Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, New York 10021, USA.
Yang
Y Y
YY
Darnell
R B
RB
D000595:Amino Acid Sequence; D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D001259:Ataxia / Q000209:etiology / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology; D001923:Brain Chemistry; D016384:Consensus Sequence; D000939:Epitopes / Q000276:immunology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009207:Myoclonus / Q000209:etiology / Q000276:immunology*; D009369:Neoplasms / Q000150:complications / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000090682:Neuro-Oncological Ventral Antigen; D009474:Neurons / Q000378:metabolism*; D015835:Ocular Motility Disorders / Q000209:etiology / Q000276:immunology*; D010257:Paraneoplastic Syndromes / Q000276:immunology*; D017354:Point Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D001323:Autoantibodies; D000939:Epitopes; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins