Kinase Subfamily NDKD

Kinase Classification: Group NDK: Subfamily NDKD

NDKD is a subfamily of Nucleoside Diphosphate Kinases with dual kinase domains and involved in cilium and microtubule function. It contains a single human gene, NME7.

Evolution

NDKD proteins are found in most animals, and scattered other species including the lower plants (several algae, moss and spike moss, but not higher plants), ciliates, excavates, oomycetes and kinetoplastids and a chytrid fungus but not other fungi. Its loss from higher plants, most fungi, and nematodes suggests a conserved role in cilium function, as those organisms have lost cilia.

Domain Structure

NDKD proteins have an N-terminal DUF1126/DM10 domain, followed by two NDK catalytic domains. Bacterial-expression human NME7 autophosphorylated, in both WT and in catalytically-dead mutants of the second domain, but not the first domain, indicating that only the first domain was active in this assay [1]. Most oomycetes have a highly divergent and partially deleted first NDK domain that is not detected by domain homology and lacks the catalytic histidine.

Functions

Human NME7 is part of the gamma-tubulin ring complex, which promotes microtubule nucleation [1]. The first (N-terminal) kinase domain autophosphorylates, and both domains are involved in complex formation. Kinase-dead mutations have reduced microtubule nucleation activity. Accordingly NME7 knockout mice have a sinus inversus defect, and hydrocephalus, likely due to defects in cilium function [2, 3], and knockdown of NME7 caused ciliary defects in a high-content cellular screen [4].

Chlamydomonas NDPK (FAP67/BUG5) has been found in the flagellar/ciliary and basal body proteomes [5, 6] and is upregulated during flagellar regeneration [7].

NME6 and NME7 have also been implicated in mouse embryonic stem cell self-renewal [8].

References

1. Liu P, Choi YK, and Qi RZ. NME7 is a functional component of the γ-tubulin ring complex. Mol Biol Cell. 2014 Jul 1;25(13):2017-25. DOI:10.1091/mbc.E13-06-0339 |
2. Vogel P, Read R, Hansen GM, Freay LC, Zambrowicz BP, and Sands AT. Situs inversus in Dpcd/Poll-/-, Nme7-/- , and Pkd1l1-/- mice. Vet Pathol. 2010 Jan;47(1):120-31. DOI:10.1177/0300985809353553 |
3. Vogel P, Read RW, Hansen GM, Payne BJ, Small D, Sands AT, and Zambrowicz BP. Congenital hydrocephalus in genetically engineered mice. Vet Pathol. 2012 Jan;49(1):166-81. DOI:10.1177/0300985811415708 |
4. Lai CK, Gupta N, Wen X, Rangell L, Chih B, Peterson AS, Bazan JF, Li L, and Scales SJ. Functional characterization of putative cilia genes by high-content analysis. Mol Biol Cell. 2011 Apr;22(7):1104-19. DOI:10.1091/mbc.E10-07-0596 |
5. Pazour GJ, Agrin N, Leszyk J, and Witman GB. Proteomic analysis of a eukaryotic cilium. J Cell Biol. 2005 Jul 4;170(1):103-13. DOI:10.1083/jcb.200504008 |
6. Keller LC, Romijn EP, Zamora I, Yates JR 3rd, and Marshall WF. Proteomic analysis of isolated chlamydomonas centrioles reveals orthologs of ciliary-disease genes. Curr Biol. 2005 Jun 21;15(12):1090-8. DOI:10.1016/j.cub.2005.05.024 |
8. Wang CH, Ma N, Lin YT, Wu CC, Hsiao M, Lu FL, Yu CC, Chen SY, and Lu J. A shRNA functional screen reveals Nme6 and Nme7 are crucial for embryonic stem cell renewal. Stem Cells. 2012 Oct;30(10):2199-211. DOI:10.1002/stem.1203 |
9. Stolc V, Samanta MP, Tongprasit W, and Marshall WF. Genome-wide transcriptional analysis of flagellar regeneration in Chlamydomonas reinhardtii identifies orthologs of ciliary disease genes. Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3703-7. DOI:10.1073/pnas.0408358102 |