Rescue of the neuroblastoma mutant of the human nucleoside diphosphate kinase A/nm23-H1 by the natural osmolyte trimethylamine-N-oxide |
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| Authors: | Florian Georgescauld Iulia Mocan Ioan Lascu |
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| Affiliation: | a Institut de Biochimie et Génétique Cellulaires, University of Bordeaux-2, CNRS, 1 Rue C. Saint-Saëns, 33077 Bordeaux Cedex, France
b UMRS 938 INSERM, Faculté de Médecine Saint Antoine, 27 Rue Chaligny, 75571 Paris, France |
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| 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 4.5-7 M urea and of 2 M TMAO. It was inactive, monomeric, contained some secondary structure but no tertiary structure and displayed a remarkable stability to denaturation. |
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| Keywords: | NDPK-HA, human nucleoside diphosphate kinase A (product of the nm23-H1 gene) S120G-NDPK-HA, S120G mutant of the human NDPK-HA BisANS, 4,4&prime -dianilino-1,1&prime -binaphthyl-5,5&prime -disulfonic acid K-pn, killer-of-prune TMAO, trimethylamine-N-oxide Ksv, the Stern-Volmer constant MG, the molten globule folding intermediate previously described MG&lowast , the folding intermediate which accumulated in the presence of 4.5-7 M urea and 2 M TMAO |
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