| Structural highlights
Function
[NDKA_HUMAN] Major role in the synthesis of nucleoside triphosphates other than ATP. Possesses nucleoside-diphosphate kinase, serine/threonine-specific protein kinase, geranyl and farnesyl pyrophosphate kinase, histidine protein kinase and 3'-5' exonuclease activities. Involved in cell proliferation, differentiation and development, signal transduction, G protein-coupled receptor endocytosis, and gene expression. Required for neural development including neural patterning and cell fate determination.[1] [2] [3]
Publication Abstract from PubMed
Nm23-H1/NDPK-A, a tumour metastasis suppressor, is a multifunctional housekeeping enzyme with nucleoside diphosphate kinase activity. Hexameric Nm23-H1 is required for suppression of tumour metastasis and it is dissociated into dimers under oxidative conditions. Here, the crystal structure of oxidized Nm23-H1 is presented. It reveals the formation of an intramolecular disulfide bond between Cys4 and Cys145 that triggers a large conformational change that destabilizes the hexameric state. The dependence of the dissociation dynamics on the H2O2 concentration was determined using hydrogen/deuterium-exchange experiments. The quaternary conformational change provides a suitable environment for the oxidation of Cys109 to sulfonic acid, as demonstrated by peptide sequencing using nanoUPLC-ESI-q-TOF tandem MS. From these and other data, it is proposed that the molecular and cellular functions of Nm23-H1 are regulated by a series of oxidative modifications coupled to its oligomeric states and that the modified cysteines are resolvable by NADPH-dependent reduction systems. These findings broaden the understanding of the complicated enzyme-regulatory mechanisms that operate under oxidative conditions.
Structure of Nm23-H1 under oxidative conditions.,Kim MS, Jeong J, Jeong J, Shin DH, Lee KJ Acta Crystallogr D Biol Crystallogr. 2013 Apr;69(Pt 4):669-80. doi:, 10.1107/S0907444913001194. Epub 2013 Mar 14. PMID:23519676[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hailat N, Keim DR, Melhem RF, Zhu XX, Eckerskorn C, Brodeur GM, Reynolds CP, Seeger RC, Lottspeich F, Strahler JR, et al.. High levels of p19/nm23 protein in neuroblastoma are associated with advanced stage disease and with N-myc gene amplification. J Clin Invest. 1991 Jul;88(1):341-5. PMID:2056128 doi:http://dx.doi.org/10.1172/JCI115299
- ↑ MacDonald NJ, Freije JM, Stracke ML, Manrow RE, Steeg PS. Site-directed mutagenesis of nm23-H1. Mutation of proline 96 or serine 120 abrogates its motility inhibitory activity upon transfection into human breast carcinoma cells. J Biol Chem. 1996 Oct 11;271(41):25107-16. PMID:8810265
- ↑ Fan Z, Beresford PJ, Oh DY, Zhang D, Lieberman J. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell. 2003 Mar 7;112(5):659-72. PMID:12628186
- ↑ Kim MS, Jeong J, Jeong J, Shin DH, Lee KJ. Structure of Nm23-H1 under oxidative conditions. Acta Crystallogr D Biol Crystallogr. 2013 Apr;69(Pt 4):669-80. doi:, 10.1107/S0907444913001194. Epub 2013 Mar 14. PMID:23519676 doi:http://dx.doi.org/10.1107/S0907444913001194
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