Kinase Subfamily NDKA

Kinase Classification: Group NDK: Subfamily NDKA

NDKA is a subfamily of Nucleoside Diphosphate Kinases which includes some with protein histidine kinase activity.

Evolution

NDKA has single members in many metazoa, including awd in Drosophila, F25H2.5 in C. elegans, and NME1-4 in vertebrates. Yeast YNK1 is also a member of this subfamily.

Domain Structure

NDKA proteins consist largely of an NDK catalytic domain, with short flanking regions. Human NME4 is localized to the mitochondrion via an cleaved N-terminal targeting sequence of ~39 AA [1] predicted by TargetP and MitoProt.

Protein Kinase Activity

NME2 (NDPK-B) was shown to phosphorylate the KCa3.1 potassium channel and the TRPV5 calcium channel on conserved histidines [2, 3] and a G protein β subunit [4]. NME1 was shown to cause phosphorylation of ATP Citrate Lyase on histidine and also reported to phosphorylate the mouse pseudokinase KSR on serine 392 [5].

Serine kinase activity was also reported for NME2 [6], though the transfer appeared to be stoichiometric (i.e. no turnover: one enzyme, one phosphorylation action) and so termed a phosphotransferase. The Drosophila homolog, awd, was also seen to autophosphorylate and transphosphorylate ovalbumin on serine [7].

Since other human histidine kinases have not been found, NDKAs may be responsible for the observed histidine phosphorylation of other proteins, including histone H4, Gβ1, annexin-1, P-selectin, and ornithine transcarbamylase.

NDKs autophosphorylate as part of their enzymatic cycle. Autophosphorylated YNK1 has been measured in yeast and shown to impede mitochondrial localization of the enzyme. Human NME1 autophosphorylation on H118 has also been detected by mass spectrometry [8]. Serine autophosphorylation of human NME1 and NME2 has also been reported [9], and NME1 autophosphorylation mapped to S44 [10], though the level of autophosphorylation is very low [11].

In addition, an aspartate kinase activity of NME1 on aldolase C protein at D319, a region with sequence similarity to both ATP citrate lyase and thiokinase [12].

NDK-1 from the fungus Neurospora crassa was also shown to autophosphorylate and transphosphorylate MBP, and is involved in light response [13]. A point mutation (P72H) greatly decreases kinase activity and blocks NDK-1 phosphorylation in vivo [14]. An NDKA member from the pea plant, Pisum sativum, involved in phototransduction, was also shown to be a protein kinase [15], and a likely NDKA from Paramecium showed autophosphorylation on histidine and serine and acid-stable (not histidine) transphosphorylation of casein [16].

References

1. Milon L, Meyer P, Chiadmi M, Munier A, Johansson M, Karlsson A, Lascu I, Capeau J, Janin J, and Lacombe ML. The human nm23-H4 gene product is a mitochondrial nucleoside diphosphate kinase. J Biol Chem. 2000 May 12;275(19):14264-72. DOI:10.1074/jbc.275.19.14264 |
2. Srivastava S, Li Z, Ko K, Choudhury P, Albaqumi M, Johnson AK, Yan Y, Backer JM, Unutmaz D, Coetzee WA, and Skolnik EY. Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. Mol Cell. 2006 Dec 8;24(5):665-675. DOI:10.1016/j.molcel.2006.11.012 |
3. Cai X, Srivastava S, Surindran S, Li Z, and Skolnik EY. Regulation of the epithelial Ca²⁺ channel TRPV5 by reversible histidine phosphorylation mediated by NDPK-B and PHPT1. Mol Biol Cell. 2014 Apr;25(8):1244-50. DOI:10.1091/mbc.E13-04-0180 |
4. Hippe HJ, Lutz S, Cuello F, Knorr K, Vogt A, Jakobs KH, Wieland T, and Niroomand F. Activation of heterotrimeric G proteins by a high energy phosphate transfer via nucleoside diphosphate kinase (NDPK) B and Gbeta subunits. Specific activation of Gsalpha by an NDPK B.Gbetagamma complex in H10 cells. J Biol Chem. 2003 Feb 28;278(9):7227-33. DOI:10.1074/jbc.M210305200 |
5. Hartsough MT, Morrison DK, Salerno M, Palmieri D, Ouatas T, Mair M, Patrick J, and Steeg PS. Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway. J Biol Chem. 2002 Aug 30;277(35):32389-99. DOI:10.1074/jbc.M203115200 |
6. Engel M, Véron M, Theisinger B, Lacombe ML, Seib T, Dooley S, and Welter C. A novel serine/threonine-specific protein phosphotransferase activity of Nm23/nucleoside-diphosphate kinase. Eur J Biochem. 1995 Nov 15;234(1):200-7. DOI:10.1111/j.1432-1033.1995.200_c.x |
7. Inoue H, Takahashi M, Oomori A, Sekiguchi M, and Yoshioka T. A novel function for nucleoside diphosphate kinase in Drosophila. Biochem Biophys Res Commun. 1996 Jan 26;218(3):887-92. DOI:10.1006/bbrc.1996.0158 |
8. Lapek JD Jr, Tombline G, and Friedman AE. Mass spectrometry detection of histidine phosphorylation on NM23-H1. J Proteome Res. 2011 Feb 4;10(2):751-5. DOI:10.1021/pr100905m |
9. Freije JM, Blay P, MacDonald NJ, Manrow RE, and Steeg PS. Site-directed mutation of Nm23-H1. Mutations lacking motility suppressive capacity upon transfection are deficient in histidine-dependent protein phosphotransferase pathways in vitro. J Biol Chem. 1997 Feb 28;272(9):5525-32. DOI:10.1074/jbc.272.9.5525 |
10. MacDonald NJ, De la Rosa A, Benedict MA, Freije JM, Krutsch H, and Steeg PS. A serine phosphorylation of Nm23, and not its nucleoside diphosphate kinase activity, correlates with suppression of tumor metastatic potential. J Biol Chem. 1993 Dec 5;268(34):25780-9.
11. Bominaar AA, Tepper AD, and Véron M. Autophosphorylation of nucleoside diphosphate kinase on non-histidine residues. FEBS Lett. 1994 Oct 10;353(1):5-8. DOI:10.1016/0014-5793(94)00997-x |
12. Wagner PD and Vu ND. Histidine to aspartate phosphotransferase activity of nm23 proteins: phosphorylation of aldolase C on Asp-319. Biochem J. 2000 Mar 15;346 Pt 3(Pt 3):623-30.
13. Ogura Y, Yoshida Y, Ichimura K, Aoyagi C, Yabe N, and Hasunuma K. Isolation and characterization of Neurospora crassa nucleoside diphosphate kinase NDK-1. Eur J Biochem. 1999 Dec;266(3):709-14. DOI:10.1046/j.1432-1327.1999.00783.x |
14. Ogura Y, Yoshida Y, Yabe N, and Hasunuma K. A point mutation in nucleoside diphosphate kinase results in a deficient light response for perithecial polarity in Neurospora crassa. J Biol Chem. 2001 Jun 15;276(24):21228-34. DOI:10.1074/jbc.M011381200 |
16. Ann KS and Nelson DL. A nucleoside diphosphate kinase from Paramecium tetraurelia with protein kinase activity. J Eukaryot Microbiol. 1996 Sep-Oct;43(5):365-72. DOI:10.1111/j.1550-7408.1996.tb05045.x |