Sequence-specific RNA binding by a Nova KH domain: implications for paraneoplastic disease and the fragile X syndrome

Cell. 2000 Feb 4;100(3):323-32. doi: 10.1016/s0092-8674(00)80668-6.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Antigens, Neoplasm*
  • Autoantigens / chemistry*
  • Binding Sites
  • Crystallography, X-Ray
  • Fragile X Syndrome / etiology*
  • Heterogeneous-Nuclear Ribonucleoprotein K
  • Models, Molecular
  • Molecular Sequence Data
  • Nerve Tissue Proteins / chemistry*
  • Neuro-Oncological Ventral Antigen
  • Paraneoplastic Syndromes, Nervous System / etiology*
  • Protein Structure, Tertiary
  • RNA-Binding Proteins / chemistry*
  • Ribonucleoproteins / chemistry*
  • Sequence Homology, Amino Acid

Substances

  • Antigens, Neoplasm
  • Autoantigens
  • Heterogeneous-Nuclear Ribonucleoprotein K
  • Nerve Tissue Proteins
  • Neuro-Oncological Ventral Antigen
  • RNA-Binding Proteins
  • Ribonucleoproteins
  • HNRNPK protein, human

Associated data

  • PDB/1EC6