Nm23-H1/NDP kinase folding intermediates and cancer: a hypothesis.
The Nm23-H1/nucleoside diphosphate (NDP) kinase A is a metastasis suppressor, besides its enzymatic activity. The mutant S120G has been found in high-grade neuroblastomas. The mutant protein, once denatured in urea, is unable to refold in vitro. A size-exclusion chromatography analysis of the folding/association pathway showed that recombinant wild-type and S120G mutant human Nm23-H1/NDP kinase A unfold and refold passing through a molten globule state while typical hexameric NDP kinases unfold without dissociated species and refold through a native monomeric intermediate. A survey of the recent literature showed that several proteins involved in cancer, and their mutants, are marginally stable, like the wild-type Nm23-H1/NDP kinase A, or are misfolded, like its S120G mutant. We therefore suggest that the low thermodynamic stability and the folding intermediate of the Nm23-H1/NDP kinase A may be necessary for its regulatory properties.
Lascu
Ioan
I
Institut de Biochimie et Génétique Cellulaires, UMR 5095 University Victor Segalen Bordeaux2 and CNRS, 1, rue Camille Saint-Saëns, 33077, Bordeaux Cedex, France. ioan.lascu@ibgc.u-bordeaux2.fr
D002850:Chromatography, Gel; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D054778:NM23 Nucleoside Diphosphate Kinases; D009447:Neuroblastoma / Q000235:genetics*; D009701:Nucleoside-Diphosphate Kinase / Q000235:genetics*; D017510:Protein Folding; D013816:Thermodynamics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D054778:NM23 Nucleoside Diphosphate Kinases; D025521:Tumor Suppressor Proteins; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase