Alternative titles; symbols
HGNC Approved Gene Symbol: NME4
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38): 16:396,729-400,754 (from NCBI)
The nucleoside diphosphate (NDP) kinases (EC 2.7.4.6) are ubiquitous enzymes that catalyze transfer of gamma-phosphates, via a phosphohistidine intermediate, between nucleoside and dioxynucleoside tri- and diphosphates. The enzymes are products of the nm23 gene family, which includes NME4 (Milon et al., 1997).
Milon et al. (1997) identified NME4, which they called nm23-H4, by screening a human stomach cDNA library. The primers were designed from a pubic database and the cDNA sequences were selected according to their homology to the human NME1 (156490) putative metastasis suppressor gene. The full-length cDNA sequence predicts a 187-amino acid protein possessing the region homologous to NDP kinases with all residues crucial for nucleotide binding and catalysis, strongly suggesting that the new gene possesses NDP kinase activity. It shares 56, 55, and 60% identity with NME1, NME2 (156491), and NME3 (601817), respectively. Compared with these other proteins, NME4 contains an additional N-terminal region that is rich in positively charged residues and could indicate routing to mitochondria. The corresponding 1.2-kb mRNA was widely distributed and expressed in tissue-dependent manner, being found at very high levels in prostate, heart, liver, small intestine, and skeletal muscle tissues, and in low amounts in the brain and in blood leukocytes.
Masse et al. (2002) cloned mouse Nme4, which they called nm23-M4. The deduced 186-amino acid protein shares 82% identity with human NME4. Northern blot analysis of several mouse tissues detected a 1.0-kb transcript only in heart, kidney, and liver.
Human NDPKD and ubiquitous MTCK (CKMT1B; 123290) are basic peripheral membrane proteins with symmetrical homooligomeric structures. Using lipid dilution assays, Epand et al. (2007) showed that NDPKD and ubiquitous MTCK facilitated lipid transfer from one bilayer to another. Lipid transfer occurred between liposomes mimicking the lipid composition of mitochondrial contact sites, containing 30 mol % cardiolipin, but transfer did not occur when cardiolipin was replaced by phosphatidylglycerol. Ubiquitous MTCK, but not NDPKD, showed some specificity in lipids transferred. Lipid transfer did not involve vesicle fusion or loss of internal contents of the liposomes.
Boissan et al. (2014) found that knockdown of nucleoside diphosphate kinases (NDPKs) NM23H1/H2, which produce GTP through ATP-driven conversion of GDP, inhibited dynamin-mediated endocytosis. NM23H1/H2 localized at clathrin-coated pits and interacted with the proline-rich domain of dynamin. In vitro, NM23H1/H2 were recruited to dynamin-induced tubules, stimulated GTP-loading on dynamin, and triggered fission in the presence of ATP and GDP. NM23H4, a mitochondria-specific NDPK, colocalized with mitochondrial dynamin-like OPA1 (605290), which is involved in mitochondria inner membrane fusion, and increased GTP-loading on OPA1. Like OPA1 loss of function, silencing of NM23H4 but not NM23H1/H2 resulted in mitochondrial fragmentation, reflecting fusion defects. Boissan et al. (2014) concluded that NDPKs interact with and provide GTP to dynamins, allowing these motor proteins to work with high thermodynamic efficiency.
Masse et al. (2002) determined that the mouse and human NME4 genes contain 5 exons and span about 3.5 kb. Their promoters, like those of other NME genes, contain several binding sites for AP2 (107580), NF1 (613113), Sp1 (189906), LEF1 (153245), and response elements to glucocorticoid receptors (138040). There are no TATA or CAAT boxes or pyrimidine-rich initiator (Inr) sequences.
Milon et al. (1997) mapped the NME4 gene to 16p13.3 by analysis of human/rodent somatic cell hybrids and by isotopic in situ hybridization.
Boissan, M., Montagnac, G., Shen, Q., Griparic, L., Guitton, J., Romao, M., Sauvonnet, N., Lagache, T., Lascu, I., Raposo, G., Desbourdes, C., Schlattner, U., Lacombe, M.-L., Polo, S., van der Bliek, A. M., Roux, A., Chavrier, P. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling. Science 344: 1510-1515, 2014. [PubMed: 24970086] [Full Text: https://doi.org/10.1126/science.1253768]
Epand, R. F., Schlattner, U., Wallimann, T., Lacombe, M.-L., Epand, R. M. Novel lipid transfer property of two mitochondrial proteins that bridge the inner and outer membranes. Biophys. J. 92: 126-137, 2007. [PubMed: 17028143] [Full Text: https://doi.org/10.1529/biophysj.106.092353]
Masse, K., Dabernat, S., Bourbon, P.-M., Larou, M., Amrein, L., Barraud, P., Perel, Y., Camara, M., Landry, M., Lacombe, M.-L., Daniel, J.-Y. Characterization of the nm23-M2, nm23-M3 and nm23-M4 mouse genes: comparison with their human homologs. Gene 296: 87-97, 2002. [PubMed: 12383506] [Full Text: https://doi.org/10.1016/s0378-1119(02)00836-3]
Milon, L., Rousseau-Merck, M.-F., Munier, A., Erent, M., Lascu, I., Capeau, J., Lacombe, M.-L. nm23-H4, a new member of the family of human nm23/nucleoside diphosphate kinase genes localised on chromosome 16p13. Hum. Genet. 99: 550-557, 1997. [PubMed: 9099850] [Full Text: https://doi.org/10.1007/s004390050405]