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Protein

Nucleoside diphosphate kinase, mitochondrial

Gene

NME4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate. Through the catalyzed exchange of gamma-phosphate between di- and triphosphonucleosides participates in regulation of intracellular nucleotide homeostasis (PubMed:10799505). Binds to anionic phospholipids, predominantly to cardiolipin; the binding inhibits its phosphotransfer activity (PubMed:18635542, PubMed:23150663). Acts as mitochondria-specific NDK; its association with cardiolipin-containing mitochondrial inner membrane is coupled to respiration suggesting that ADP locally regenerated in the mitochondrion innermembrane space by its activity is directly taken up via ANT ADP/ATP translocase into the matrix space to stimulate respiratory ATP regeneration (PubMed:18635542). Proposed to increase GTP-loading on dynamin-related GTPase OPA1 in mitochondria (PubMed:24970086). In vitro can induce liposome cross-linking suggesting that it can cross-link inner and outer membranes to form contact sites, and promotes intermembrane migration of anionic phosphoplipids. Promotes the redistribution of cardiolipin between the mitochondrial inner membrane and outer membrane which is implicated in pro-apoptotic signaling (PubMed:18635542, PubMed:17028143, PubMed:23150663).Curated4 Publications

Catalytic activityi

ATP + nucleoside diphosphate = ADP + nucleoside triphosphate.

Cofactori

Mg2+By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei45 – 451ATPBy similarity
Binding sitei93 – 931ATPBy similarity
Binding sitei121 – 1211ATPBy similarity
Binding sitei127 – 1271ATPBy similarity
Binding sitei138 – 1381ATPBy similarity
Binding sitei148 – 1481ATPBy similarity
Active sitei151 – 1511Pros-phosphohistidine intermediateBy similarity

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Transferase

Keywords - Biological processi

Lipid transport, Nucleotide metabolism, Transport

Keywords - Ligandi

ATP-binding, Lipid-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.4.6. 2681.
ReactomeiREACT_21330. Synthesis and interconversion of nucleotide di- and triphosphates.

Names & Taxonomyi

Protein namesi
Recommended name:
Nucleoside diphosphate kinase, mitochondrial (EC:2.7.4.6)
Short name:
NDK
Short name:
NDP kinase, mitochondrial
Alternative name(s):
Nucleoside diphosphate kinase D
Short name:
NDPKD
nm23-H4
Gene namesi
Name:NME4
Synonyms:NM23D
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 16

Organism-specific databases

HGNCiHGNC:7852. NME4.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Membrane, Mitochondrion

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi90 – 901R → D: Abolishes cardiolipin-containing membrane binding; decreases lipid transfer and pro-apoptotic activity; does not change phosphotransfer activity. 2 Publications

Organism-specific databases

PharmGKBiPA31657.

Polymorphism and mutation databases

BioMutaiNME4.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transit peptidei1 – 3333Mitochondrion1 PublicationAdd
BLAST
Chaini34 – 187154Nucleoside diphosphate kinase, mitochondrialPRO_0000019432Add
BLAST

Proteomic databases

MaxQBiO00746.
PaxDbiO00746.
PRIDEiO00746.

PTM databases

PhosphoSiteiO00746.

Expressioni

Tissue specificityi

Widely distributed. 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.

Gene expression databases

BgeeiO00746.
CleanExiHS_NME4.
ExpressionAtlasiO00746. baseline and differential.
GenevisibleiO00746. HS.

Organism-specific databases

HPAiCAB045996.
CAB045997.

Interactioni

Subunit structurei

Homohexamer (PubMed:10799505). Interacts with OPA1 (PubMed:23150663). Interacts with CAPN8 (By similarity).By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
HTTP428582EBI-744871,EBI-466029
NME1P155314EBI-744871,EBI-741141

Protein-protein interaction databases

BioGridi110897. 23 interactions.
IntActiO00746. 11 interactions.
MINTiMINT-1445974.
STRINGi9606.ENSP00000219479.

Structurei

Secondary structure

1
187
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi35 – 373Combined sources
Beta strandi39 – 446Combined sources
Helixi46 – 505Combined sources
Helixi54 – 6310Combined sources
Beta strandi67 – 748Combined sources
Helixi78 – 847Combined sources
Helixi86 – 883Combined sources
Helixi94 – 1018Combined sources
Beta strandi106 – 1138Combined sources
Helixi116 – 1249Combined sources
Helixi129 – 1313Combined sources
Helixi137 – 1415Combined sources
Beta strandi149 – 1524Combined sources
Helixi156 – 16611Combined sources
Helixi169 – 1713Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1EHWX-ray2.40A/B33-175[»]
ProteinModelPortaliO00746.
SMRiO00746. Positions 36-175.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO00746.

Family & Domainsi

Sequence similaritiesi

Belongs to the NDK family.Curated

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiCOG0105.
GeneTreeiENSGT00760000119146.
HOGENOMiHOG000224564.
HOVERGENiHBG000423.
InParanoidiO00746.
KOiK00940.
OrthoDBiEOG7GJ6FG.
PhylomeDBiO00746.
TreeFamiTF106373.

Family and domain databases

Gene3Di3.30.70.141. 1 hit.
HAMAPiMF_00451. NDP_kinase.
InterProiIPR001564. Nucleoside_diP_kinase.
IPR023005. Nucleoside_diP_kinase_AS.
[Graphical view]
PfamiPF00334. NDK. 1 hit.
[Graphical view]
PRINTSiPR01243. NUCDPKINASE.
SMARTiSM00562. NDK. 1 hit.
[Graphical view]
SUPFAMiSSF54919. SSF54919. 1 hit.
PROSITEiPS00469. NDP_KINASES. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O00746-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MGGLFWRSAL RGLRCGPRAP GPSLLVRHGS GGPSWTRERT LVAVKPDGVQ
60 70 80 90 100
RRLVGDVIQR FERRGFTLVG MKMLQAPESV LAEHYQDLRR KPFYPALIRY
110 120 130 140 150
MSSGPVVAMV WEGYNVVRAS RAMIGHTDSA EAAPGTIRGD FSVHISRNVI
160 170 180
HASDSVEGAQ REIQLWFQSS ELVSWADGGQ HSSIHPA
Length:187
Mass (Da):20,659
Last modified:July 1, 1997 - v1
Checksum:iA56FEF18A7D712D4
GO
Isoform 2 (identifier: O00746-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-70: Missing.

Note: No experimental confirmation available. Gene prediction based on EST data.
Show »
Length:117
Mass (Da):12,979
Checksum:i3B885B828E3C1042
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 7070Missing in isoform 2. CuratedVSP_054743Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y07604 mRNA. Translation: CAA68877.1.
BT019438 mRNA. Translation: AAV38245.1.
AE006463 Genomic DNA. Translation: AAK61230.1.
Z97634 Genomic DNA. Translation: CAC37288.1.
CH471112 Genomic DNA. Translation: EAW85818.1.
CH471112 Genomic DNA. Translation: EAW85819.1.
CH471112 Genomic DNA. Translation: EAW85820.1.
BC004880 mRNA. Translation: AAH04880.1.
BC017067 mRNA. Translation: AAH17067.1.
CCDSiCCDS10408.1. [O00746-1]
CCDS66886.1. [O00746-2]
RefSeqiNP_001273362.1. NM_001286433.1.
NP_001273364.1. NM_001286435.1.
NP_001273365.1. NM_001286436.1. [O00746-2]
NP_001273367.1. NM_001286438.1. [O00746-2]
NP_001273368.1. NM_001286439.1. [O00746-2]
NP_001273369.1. NM_001286440.1. [O00746-2]
NP_005000.1. NM_005009.2. [O00746-1]
UniGeneiHs.9235.

Genome annotation databases

EnsembliENST00000219479; ENSP00000219479; ENSG00000103202. [O00746-1]
ENST00000397722; ENSP00000380834; ENSG00000103202. [O00746-2]
ENST00000450036; ENSP00000389048; ENSG00000103202. [O00746-2]
ENST00000620944; ENSP00000479996; ENSG00000103202. [O00746-2]
GeneIDi4833.
KEGGihsa:4833.
UCSCiuc002cgz.3. human. [O00746-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y07604 mRNA. Translation: CAA68877.1.
BT019438 mRNA. Translation: AAV38245.1.
AE006463 Genomic DNA. Translation: AAK61230.1.
Z97634 Genomic DNA. Translation: CAC37288.1.
CH471112 Genomic DNA. Translation: EAW85818.1.
CH471112 Genomic DNA. Translation: EAW85819.1.
CH471112 Genomic DNA. Translation: EAW85820.1.
BC004880 mRNA. Translation: AAH04880.1.
BC017067 mRNA. Translation: AAH17067.1.
CCDSiCCDS10408.1. [O00746-1]
CCDS66886.1. [O00746-2]
RefSeqiNP_001273362.1. NM_001286433.1.
NP_001273364.1. NM_001286435.1.
NP_001273365.1. NM_001286436.1. [O00746-2]
NP_001273367.1. NM_001286438.1. [O00746-2]
NP_001273368.1. NM_001286439.1. [O00746-2]
NP_001273369.1. NM_001286440.1. [O00746-2]
NP_005000.1. NM_005009.2. [O00746-1]
UniGeneiHs.9235.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1EHWX-ray2.40A/B33-175[»]
ProteinModelPortaliO00746.
SMRiO00746. Positions 36-175.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi110897. 23 interactions.
IntActiO00746. 11 interactions.
MINTiMINT-1445974.
STRINGi9606.ENSP00000219479.

PTM databases

PhosphoSiteiO00746.

Polymorphism and mutation databases

BioMutaiNME4.

Proteomic databases

MaxQBiO00746.
PaxDbiO00746.
PRIDEiO00746.

Protocols and materials databases

DNASUi4833.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000219479; ENSP00000219479; ENSG00000103202. [O00746-1]
ENST00000397722; ENSP00000380834; ENSG00000103202. [O00746-2]
ENST00000450036; ENSP00000389048; ENSG00000103202. [O00746-2]
ENST00000620944; ENSP00000479996; ENSG00000103202. [O00746-2]
GeneIDi4833.
KEGGihsa:4833.
UCSCiuc002cgz.3. human. [O00746-1]

Organism-specific databases

CTDi4833.
GeneCardsiGC16P000446.
H-InvDBHIX0012647.
HGNCiHGNC:7852. NME4.
HPAiCAB045996.
CAB045997.
MIMi601818. gene.
neXtProtiNX_O00746.
PharmGKBiPA31657.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiCOG0105.
GeneTreeiENSGT00760000119146.
HOGENOMiHOG000224564.
HOVERGENiHBG000423.
InParanoidiO00746.
KOiK00940.
OrthoDBiEOG7GJ6FG.
PhylomeDBiO00746.
TreeFamiTF106373.

Enzyme and pathway databases

BRENDAi2.7.4.6. 2681.
ReactomeiREACT_21330. Synthesis and interconversion of nucleotide di- and triphosphates.

Miscellaneous databases

ChiTaRSiNME4. human.
EvolutionaryTraceiO00746.
GeneWikiiNME4.
GenomeRNAii4833.
NextBioi18626.
PROiO00746.
SOURCEiSearch...

Gene expression databases

BgeeiO00746.
CleanExiHS_NME4.
ExpressionAtlasiO00746. baseline and differential.
GenevisibleiO00746. HS.

Family and domain databases

Gene3Di3.30.70.141. 1 hit.
HAMAPiMF_00451. NDP_kinase.
InterProiIPR001564. Nucleoside_diP_kinase.
IPR023005. Nucleoside_diP_kinase_AS.
[Graphical view]
PfamiPF00334. NDK. 1 hit.
[Graphical view]
PRINTSiPR01243. NUCDPKINASE.
SMARTiSM00562. NDK. 1 hit.
[Graphical view]
SUPFAMiSSF54919. SSF54919. 1 hit.
PROSITEiPS00469. NDP_KINASES. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "nm23-H4, a new member of the family of human nm23/nucleoside diphosphate kinase genes localised on chromosome 16p13."
    Milon L., Rousseau-Merck M.-F., Munier A., Erent M., Lascu I., Capeau J., Lacombe M.-L.
    Hum. Genet. 99:550-557(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE.
    Tissue: Stomach.
  2. "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
    Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
    Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
  3. "Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16."
    Daniels R.J., Peden J.F., Lloyd C., Horsley S.W., Clark K., Tufarelli C., Kearney L., Buckle V.J., Doggett N.A., Flint J., Higgs D.R.
    Hum. Mol. Genet. 10:339-352(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  5. "The sequence and analysis of duplication-rich human chromosome 16."
    Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.
    , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A.
    Nature 432:988-994(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Skin and Uterus.
  7. "Novel lipid transfer property of two mitochondrial proteins that bridge the inner and outer membranes."
    Epand R.F., Schlattner U., Wallimann T., Lacombe M.L., Epand R.M.
    Biophys. J. 92:126-137(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  8. "The nucleoside diphosphate kinase D (NM23-H4) binds the inner mitochondrial membrane with high affinity to cardiolipin and couples nucleotide transfer with respiration."
    Tokarska-Schlattner M., Boissan M., Munier A., Borot C., Mailleau C., Speer O., Schlattner U., Lacombe M.L.
    J. Biol. Chem. 283:26198-26207(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, FUNCTION, PHOSPHOLIPID-BINDING, MUTAGENESIS OF ARG-90.
  9. "Dual function of mitochondrial Nm23-H4 protein in phosphotransfer and intermembrane lipid transfer: a cardiolipin-dependent switch."
    Schlattner U., Tokarska-Schlattner M., Ramirez S., Tyurina Y.Y., Amoscato A.A., Mohammadyani D., Huang Z., Jiang J., Yanamala N., Seffouh A., Boissan M., Epand R.F., Epand R.M., Klein-Seetharaman J., Lacombe M.L., Kagan V.E.
    J. Biol. Chem. 288:111-121(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF ARG-90, INTERACTION WITH OPA1.
  10. "Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling."
    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.
    Science 344:1510-1515(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION.
  11. "The human nm23-H4 gene product is a mitochondrial nucleoside diphosphate kinase."
    Milon L., Meyer P., Chiadmi M., Munier A., Johansson M., Karlsson A., Lascu I., Capeau J., Janin J., Lacombe M.-L.
    J. Biol. Chem. 275:14264-14272(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), CHARACTERIZATION.

Entry informationi

Entry nameiNDKM_HUMAN
AccessioniPrimary (citable) accession number: O00746
Secondary accession number(s): A2IDD0, Q5U0M9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: July 1, 1997
Last modified: June 24, 2015
This is version 151 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 16
    Human chromosome 16: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.