Rescue of the neuroblastoma mutant of the human nucleoside diphosphate kinase A/nm23-H1 by the natural osmolyte trimethylamine-N-oxide

FEBS Lett. 2009 Feb 18;583(4):820-4. doi: 10.1016/j.febslet.2009.01.043. Epub 2009 Jan 30.

Abstract

The point mutation S120G in human nucleoside diphosphate kinase A, identified in patients with neuroblastoma, causes a protein folding defect. The urea-unfolded protein cannot refold in vitro, and accumulates as a molten globule folding intermediate. We show here that the trimethylamine-N-oxide (TMAO) corrects the folding defect and stimulated subunit association. TMAO also substantially increased the stability to denaturation by urea of both wild-type and S120G mutant. A non-native folding intermediate accumulated in the presence of 4.5-7M urea and of 2M TMAO. It was inactive, monomeric, contained some secondary structure but no tertiary structure and displayed a remarkable stability to denaturation.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Kinetics
  • Methylamines / metabolism*
  • NM23 Nucleoside Diphosphate Kinases / genetics
  • NM23 Nucleoside Diphosphate Kinases / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neuroblastoma / genetics*
  • Point Mutation*
  • Protein Folding / drug effects
  • Urea / pharmacology

Substances

  • Methylamines
  • NM23 Nucleoside Diphosphate Kinases
  • Neoplasm Proteins
  • Urea
  • NME1 protein, human
  • trimethyloxamine