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P22413

- ENPP1_HUMAN

UniProt

P22413 - ENPP1_HUMAN

Protein

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1

Gene

ENPP1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 164 (01 Oct 2014)
      Sequence version 2 (19 Sep 2002)
      Previous versions | rss
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    Functioni

    By generating PPi, plays a role in regulating pyrophosphate levels, and functions in bone mineralization and soft tissue calcification. PPi inhibits mineralization by binding to nascent hydroxyapatite (HA) crystals, thereby preventing further growth of these crystals. Preferentially hydrolyzes ATP, but can also hydrolyze other nucleoside 5' triphosphates such as GTP, CTP, TTP and UTP to their corresponding monophosphates with release of pyrophosphate and diadenosine polyphosphates, and also 3',5'-cAMP to AMP. May also be involved in the regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, and the regulation of purinergic signaling. Appears to modulate insulin sensitivity and function.2 Publications

    Catalytic activityi

    Hydrolytically removes 5'-nucleotides successively from the 3'-hydroxy termini of 3'-hydroxy-terminated oligonucleotides.1 Publication
    A dinucleotide + H2O = 2 mononucleotides.1 Publication

    Cofactori

    Binds 2 zinc ions per subunit.By similarity

    Enzyme regulationi

    At low concentrations of ATP, a phosphorylated intermediate is formed which inhibits further hydrolysis.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei102 – 1032CleavageBy similarity
    Metal bindingi218 – 2181Zinc 1; catalyticBy similarity
    Active sitei256 – 2561AMP-threonine intermediateBy similarity
    Metal bindingi256 – 2561Zinc 1; catalyticBy similarity
    Binding sitei277 – 2771SubstrateBy similarity
    Binding sitei295 – 2951SubstrateBy similarity
    Binding sitei340 – 3401SubstrateBy similarity
    Metal bindingi376 – 3761Zinc 2; catalyticBy similarity
    Metal bindingi380 – 3801Zinc 2; via tele nitrogen; catalyticBy similarity
    Metal bindingi423 – 4231Zinc 1; catalyticBy similarity
    Metal bindingi424 – 4241Zinc 1; via tele nitrogen; catalyticBy similarity
    Metal bindingi535 – 5351Zinc 2; via tele nitrogen; catalyticBy similarity
    Metal bindingi800 – 8001CalciumBy similarity
    Metal bindingi802 – 8021CalciumBy similarity
    Metal bindingi804 – 8041CalciumBy similarity
    Metal bindingi806 – 8061Calcium; via carbonyl oxygenBy similarity
    Metal bindingi808 – 8081CalciumBy similarity
    Sitei915 – 9151Essential for catalytic activityBy similarity

    GO - Molecular functioni

    1. 3'-phosphoadenosine 5'-phosphosulfate binding Source: BHF-UCL
    2. ATP binding Source: BHF-UCL
    3. calcium ion binding Source: UniProtKB
    4. insulin receptor binding Source: BHF-UCL
    5. NADH pyrophosphatase activity Source: UniProtKB-EC
    6. nucleic acid binding Source: InterPro
    7. nucleoside-triphosphate diphosphatase activity Source: BHF-UCL
    8. nucleotide diphosphatase activity Source: BHF-UCL
    9. phosphodiesterase I activity Source: UniProtKB
    10. polysaccharide binding Source: InterPro
    11. protein binding Source: IntAct
    12. protein homodimerization activity Source: BHF-UCL
    13. scavenger receptor activity Source: InterPro
    14. zinc ion binding Source: UniProtKB

    GO - Biological processi

    1. 3'-phosphoadenosine 5'-phosphosulfate metabolic process Source: BHF-UCL
    2. ATP catabolic process Source: UniProtKB
    3. biomineral tissue development Source: UniProtKB-KW
    4. bone remodeling Source: Ensembl
    5. cellular phosphate ion homeostasis Source: BHF-UCL
    6. cellular response to insulin stimulus Source: BHF-UCL
    7. generation of precursor metabolites and energy Source: BHF-UCL
    8. immune response Source: InterPro
    9. inorganic diphosphate transport Source: BHF-UCL
    10. negative regulation of cell growth Source: BHF-UCL
    11. negative regulation of fat cell differentiation Source: BHF-UCL
    12. negative regulation of glucose import Source: BHF-UCL
    13. negative regulation of glycogen biosynthetic process Source: BHF-UCL
    14. negative regulation of insulin receptor signaling pathway Source: BHF-UCL
    15. negative regulation of ossification Source: Ensembl
    16. negative regulation of protein autophosphorylation Source: BHF-UCL
    17. nucleic acid phosphodiester bond hydrolysis Source: GOC
    18. nucleoside triphosphate catabolic process Source: BHF-UCL
    19. phosphate-containing compound metabolic process Source: BHF-UCL
    20. regulation of bone mineralization Source: BHF-UCL
    21. riboflavin metabolic process Source: Reactome
    22. sequestering of triglyceride Source: BHF-UCL
    23. small molecule metabolic process Source: Reactome
    24. vitamin metabolic process Source: Reactome
    25. water-soluble vitamin metabolic process Source: Reactome

    Keywords - Molecular functioni

    Hydrolase

    Keywords - Biological processi

    Biomineralization

    Keywords - Ligandi

    Calcium, Metal-binding, Zinc

    Enzyme and pathway databases

    ReactomeiREACT_11070. Vitamin B2 (riboflavin) metabolism.
    SABIO-RKP22413.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Ectonucleotide pyrophosphatase/phosphodiesterase family member 1
    Short name:
    E-NPP 1
    Alternative name(s):
    Membrane component chromosome 6 surface marker 1
    Phosphodiesterase I/nucleotide pyrophosphatase 1
    Plasma-cell membrane glycoprotein PC-1
    Including the following 2 domains:
    Alkaline phosphodiesterase I (EC:3.1.4.1)
    Nucleotide pyrophosphatase (EC:3.6.1.9)
    Short name:
    NPPase
    Gene namesi
    Name:ENPP1
    Synonyms:M6S1, NPPS, PC1, PDNP1
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 6

    Organism-specific databases

    HGNCiHGNC:3356. ENPP1.

    Subcellular locationi

    Cell membrane; Single-pass type II membrane protein. Basolateral cell membrane; Single-pass type II membrane protein. Secreted By similarity
    Note: The proteolytically processed form is secreted By similarity. Targeted to the basolateral membrane in polarized epithelial cells and in hepatocytes, and to matrix vesicles in osteoblasts. In bile duct cells and cancer cells, located to the apical cytoplasmic side.By similarity

    GO - Cellular componenti

    1. basolateral plasma membrane Source: BHF-UCL
    2. cell surface Source: BHF-UCL
    3. extracellular space Source: BHF-UCL
    4. integral component of membrane Source: UniProtKB
    5. integral component of plasma membrane Source: UniProtKB
    6. lysosomal membrane Source: UniProtKB
    7. plasma membrane Source: BHF-UCL

    Keywords - Cellular componenti

    Cell membrane, Membrane, Secreted

    Pathology & Biotechi

    Involvement in diseasei

    Ossification of the posterior longitudinal ligament of the spine (OPLL) [MIM:602475]: A calcification of the posterior longitudinal ligament of the spinal column, usually at the level of the cervical spine. Patients with OPLL frequently present with a severe myelopathy that can lead to tetraparesis.1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti91 – 911L → P in OPLL. 1 Publication
    VAR_014141
    Natural varianti287 – 2871S → F in OPLL. 1 Publication
    Corresponds to variant rs190947144 [ dbSNP | Ensembl ].
    VAR_014143
    Arterial calcification of infancy, generalized, 1 (GACI1) [MIM:208000]: A severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. The disorder is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure.4 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti250 – 2501P → L in GACI1. 1 Publication
    VAR_067910
    Natural varianti252 – 2521Missing in GACI1. 1 Publication
    VAR_067911
    Natural varianti305 – 3051P → T in GACI1. 1 Publication
    VAR_067912
    Natural varianti342 – 3421G → V in GACI1. 2 Publications
    VAR_037433
    Natural varianti371 – 3711Y → F in GACI1; unknown pathological significance. 2 Publications
    VAR_037434
    Natural varianti538 – 5381D → H in GACI1. 1 Publication
    VAR_067913
    Natural varianti579 – 5791L → F in GACI1. 1 Publication
    VAR_018514
    Natural varianti586 – 5861G → R in GACI1. 1 Publication
    VAR_067914
    Natural varianti774 – 7741R → C in GACI1; unknown pathological significance. 2 Publications
    Corresponds to variant rs28933977 [ dbSNP | Ensembl ].
    VAR_018515
    Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.
    Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti173 – 1731K → Q Associated with NIDDM. 4 Publications
    Corresponds to variant rs1044498 [ dbSNP | Ensembl ].
    VAR_008873
    Hypophosphatemic rickets, autosomal recessive, 2 (ARHR2) [MIM:613312]: A hereditary form of hypophosphatemic rickets, a disorder of proximal renal tubule function that causes phosphate loss, hypophosphatemia and skeletal deformities, including rickets and osteomalacia unresponsive to vitamin D. Symptoms are bone pain, fractures and growth abnormalities.2 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti266 – 2661G → V in ARHR2. 1 Publication
    Corresponds to variant rs121908248 [ dbSNP | Ensembl ].
    VAR_063719
    Natural varianti901 – 9011Y → S in ARHR2; loss of activity. 1 Publication
    Corresponds to variant rs121908249 [ dbSNP | Ensembl ].
    VAR_063720
    Cole disease (COLED) [MIM:615522]: A rare autosomal dominant genodermatosis characterized by punctate keratoderma associated with irregularly shaped hypopigmented macules, which are typically found over the arms and legs but not the trunk or acral regions. Skin biopsies of palmoplantar lesions show hyperorthokeratosis, hypergranulosis, and acanthosis. Hypopigmented areas of skin, however, reveal a reduction in melanin content in keratinocytes but not in melanocytes, as well as hyperkeratosis and a normal number of melanocytes. Ultrastructurally, melanocytes show a disproportionately large number of melanosomes in the cytoplasm and dendrites, whereas keratinocytes show a paucity of these organelles, suggestive of impaired melanosome transfer. Some patients also exhibit calcinosis cutis or calcific tendinopathy.1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti149 – 1491C → S in COLED. 1 Publication
    VAR_070782
    Natural varianti164 – 1641C → S in COLED. 1 Publication
    VAR_070783
    Natural varianti177 – 1771C → Y in COLED. 1 Publication
    VAR_070784

    Keywords - Diseasei

    Diabetes mellitus, Disease mutation, Obesity

    Organism-specific databases

    MIMi125853. phenotype.
    208000. phenotype.
    602475. phenotype.
    613312. phenotype.
    615522. phenotype.
    Orphaneti289176. Autosomal recessive hypophosphatemic rickets.
    51608. Generalized arterial calcification of infancy.
    324561. Hypopigmentation-punctate palmoplantar keratoderma syndrome.
    PharmGKBiPA27791.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 925925Ectonucleotide pyrophosphatase/phosphodiesterase family member 1PRO_0000188564Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi108 ↔ 122PROSITE-ProRule annotation
    Disulfide bondi112 ↔ 140PROSITE-ProRule annotation
    Disulfide bondi120 ↔ 133PROSITE-ProRule annotation
    Disulfide bondi126 ↔ 132PROSITE-ProRule annotation
    Disulfide bondi149 ↔ 166PROSITE-ProRule annotation
    Disulfide bondi154 ↔ 184PROSITE-ProRule annotation
    Disulfide bondi164 ↔ 177PROSITE-ProRule annotation
    Disulfide bondi170 ↔ 176PROSITE-ProRule annotation
    Glycosylationi179 – 1791N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi195 ↔ 241PROSITE-ProRule annotation
    Disulfide bondi203 ↔ 415PROSITE-ProRule annotation
    Glycosylationi285 – 2851N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi341 – 3411N-linked (GlcNAc...)3 Publications
    Disulfide bondi431 ↔ 530PROSITE-ProRule annotation
    Glycosylationi477 – 4771N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi480 ↔ 868PROSITE-ProRule annotation
    Glycosylationi585 – 5851N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi614 ↔ 672PROSITE-ProRule annotation
    Disulfide bondi626 ↔ 726PROSITE-ProRule annotation
    Disulfide bondi628 ↔ 711PROSITE-ProRule annotation
    Glycosylationi643 – 6431N-linked (GlcNAc...)2 Publications
    Glycosylationi700 – 7001N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi731 – 7311N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi748 – 7481N-linked (GlcNAc...)2 Publications
    Disulfide bondi838 ↔ 848PROSITE-ProRule annotation

    Post-translational modificationi

    Autophosphorylated as part of the catalytic cycle of phosphodiesterase/pyrophosphatase activity.
    N-glycosylated.3 Publications
    A secreted form is produced through cleavage at Lys-103 by intracellular processing.By similarity

    Keywords - PTMi

    Disulfide bond, Glycoprotein

    Proteomic databases

    MaxQBiP22413.
    PaxDbiP22413.
    PRIDEiP22413.

    PTM databases

    PhosphoSiteiP22413.

    Expressioni

    Tissue specificityi

    Expressed in plasma cells and also in a number of non-lymphoid tissues, including the distal convoluted tubule of the kidney, chondrocytes and epididymis.1 Publication

    Gene expression databases

    ArrayExpressiP22413.
    BgeeiP22413.
    CleanExiHS_ENPP1.
    GenevestigatoriP22413.

    Organism-specific databases

    HPAiCAB032904.

    Interactioni

    Subunit structurei

    The secreted form is monomeric By similarity. Homodimer. Interacts with INSR.By similarity1 Publication

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    INSRP062132EBI-3197846,EBI-475899

    Protein-protein interaction databases

    BioGridi111193. 3 interactions.
    IntActiP22413. 3 interactions.
    STRINGi9606.ENSP00000354238.

    Structurei

    Secondary structure

    1
    925
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Turni151 – 1555
    Beta strandi163 – 1653
    Helixi168 – 1736
    Helixi180 – 1834

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2YS0NMR-A147-189[»]
    ProteinModelPortaliP22413.
    SMRiP22413. Positions 106-922.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP22413.

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini1 – 7676CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini98 – 925828ExtracellularSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei77 – 9721Helical; Signal-anchor for type II membrane proteinSequence AnalysisAdd
    BLAST

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini104 – 14441SMB 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini145 – 18945SMB 2PROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni191 – 591401PhosphodiesteraseAdd
    BLAST
    Regioni597 – 64751LinkerBy similarityAdd
    BLAST
    Regioni654 – 925272NucleaseAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi45 – 528Di-leucine motif

    Domaini

    The di-leucine motif is required for basolateral targeting in epithelial cells, and for targeting to matrix vesicles derived from mineralizing cells.By similarity

    Sequence similaritiesi

    Contains 2 SMB (somatomedin-B) domains.Curated

    Keywords - Domaini

    Repeat, Signal-anchor, Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiCOG1524.
    HOGENOMiHOG000037439.
    HOVERGENiHBG051484.
    InParanoidiP22413.
    KOiK01513.
    OMAiFEERILA.
    OrthoDBiEOG7XM2X4.
    PhylomeDBiP22413.
    TreeFamiTF330032.

    Family and domain databases

    Gene3Di3.40.570.10. 1 hit.
    3.40.720.10. 1 hit.
    InterProiIPR017849. Alkaline_Pase-like_a/b/a.
    IPR017850. Alkaline_phosphatase_core.
    IPR001604. DNA/RNA_non-sp_Endonuclease.
    IPR024873. E-NPP.
    IPR020821. Extracellular_endonuc_su_A.
    IPR002591. Phosphodiest/P_Trfase.
    IPR020436. Somatomedin_B_chordata.
    IPR001212. Somatomedin_B_dom.
    [Graphical view]
    PANTHERiPTHR10151. PTHR10151. 1 hit.
    PfamiPF01223. Endonuclease_NS. 1 hit.
    PF01663. Phosphodiest. 1 hit.
    PF01033. Somatomedin_B. 2 hits.
    [Graphical view]
    PRINTSiPR00022. SOMATOMEDINB.
    SMARTiSM00892. Endonuclease_NS. 1 hit.
    SM00477. NUC. 1 hit.
    SM00201. SO. 2 hits.
    [Graphical view]
    SUPFAMiSSF53649. SSF53649. 1 hit.
    PROSITEiPS00524. SMB_1. 2 hits.
    PS50958. SMB_2. 2 hits.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P22413-1 [UniParc]FASTAAdd to Basket

    « Hide

    MERDGCAGGG SRGGEGGRAP REGPAGNGRD RGRSHAAEAP GDPQAAASLL    50
    APMDVGEEPL EKAARARTAK DPNTYKVLSL VLSVCVLTTI LGCIFGLKPS 100
    CAKEVKSCKG RCFERTFGNC RCDAACVELG NCCLDYQETC IEPEHIWTCN 150
    KFRCGEKRLT RSLCACSDDC KDKGDCCINY SSVCQGEKSW VEEPCESINE 200
    PQCPAGFETP PTLLFSLDGF RAEYLHTWGG LLPVISKLKK CGTYTKNMRP 250
    VYPTKTFPNH YSIVTGLYPE SHGIIDNKMY DPKMNASFSL KSKEKFNPEW 300
    YKGEPIWVTA KYQGLKSGTF FWPGSDVEIN GIFPDIYKMY NGSVPFEERI 350
    LAVLQWLQLP KDERPHFYTL YLEEPDSSGH SYGPVSSEVI KALQRVDGMV 400
    GMLMDGLKEL NLHRCLNLIL ISDHGMEQGS CKKYIYLNKY LGDVKNIKVI 450
    YGPAARLRPS DVPDKYYSFN YEGIARNLSC REPNQHFKPY LKHFLPKRLH 500
    FAKSDRIEPL TFYLDPQWQL ALNPSERKYC GSGFHGSDNV FSNMQALFVG 550
    YGPGFKHGIE ADTFENIEVY NLMCDLLNLT PAPNNGTHGS LNHLLKNPVY 600
    TPKHPKEVHP LVQCPFTRNP RDNLGCSCNP SILPIEDFQT QFNLTVAEEK 650
    IIKHETLPYG RPRVLQKENT ICLLSQHQFM SGYSQDILMP LWTSYTVDRN 700
    DSFSTEDFSN CLYQDFRIPL SPVHKCSFYK NNTKVSYGFL SPPQLNKNSS 750
    GIYSEALLTT NIVPMYQSFQ VIWRYFHDTL LRKYAEERNG VNVVSGPVFD 800
    FDYDGRCDSL ENLRQKRRVI RNQEILIPTH FFIVLTSCKD TSQTPLHCEN 850
    LDTLAFILPH RTDNSESCVH GKHDSSWVEE LLMLHRARIT DVEHITGLSF 900
    YQQRKEPVSD ILKLKTHLPT FSQED 925
    Length:925
    Mass (Da):104,924
    Last modified:September 19, 2002 - v2
    Checksum:i0ECAA063801CAFEB
    GO

    Sequence cautioni

    The sequence AAA63237.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.
    The sequence AAH59375.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.
    The sequence BAA02054.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti91 – 911L → P in OPLL. 1 Publication
    VAR_014141
    Natural varianti149 – 1491C → S in COLED. 1 Publication
    VAR_070782
    Natural varianti164 – 1641C → S in COLED. 1 Publication
    VAR_070783
    Natural varianti173 – 1731K → Q Associated with NIDDM. 4 Publications
    Corresponds to variant rs1044498 [ dbSNP | Ensembl ].
    VAR_008873
    Natural varianti177 – 1771C → Y in COLED. 1 Publication
    VAR_070784
    Natural varianti179 – 1791N → S.
    Corresponds to variant rs2273411 [ dbSNP | Ensembl ].
    VAR_037432
    Natural varianti250 – 2501P → L in GACI1. 1 Publication
    VAR_067910
    Natural varianti252 – 2521Missing in GACI1. 1 Publication
    VAR_067911
    Natural varianti266 – 2661G → V in ARHR2. 1 Publication
    Corresponds to variant rs121908248 [ dbSNP | Ensembl ].
    VAR_063719
    Natural varianti268 – 2681Y → H.1 Publication
    Corresponds to variant rs1805139 [ dbSNP | Ensembl ].
    VAR_014142
    Natural varianti287 – 2871S → F in OPLL. 1 Publication
    Corresponds to variant rs190947144 [ dbSNP | Ensembl ].
    VAR_014143
    Natural varianti305 – 3051P → T in GACI1. 1 Publication
    VAR_067912
    Natural varianti342 – 3421G → V in GACI1. 2 Publications
    VAR_037433
    Natural varianti371 – 3711Y → F in GACI1; unknown pathological significance. 2 Publications
    VAR_037434
    Natural varianti538 – 5381D → H in GACI1. 1 Publication
    VAR_067913
    Natural varianti579 – 5791L → F in GACI1. 1 Publication
    VAR_018514
    Natural varianti586 – 5861G → R in GACI1. 1 Publication
    VAR_067914
    Natural varianti774 – 7741R → C in GACI1; unknown pathological significance. 2 Publications
    Corresponds to variant rs28933977 [ dbSNP | Ensembl ].
    VAR_018515
    Natural varianti779 – 7791T → P.1 Publication
    Corresponds to variant rs1805138 [ dbSNP | Ensembl ].
    VAR_014144
    Natural varianti886 – 8861R → T.
    Corresponds to variant rs8192683 [ dbSNP | Ensembl ].
    VAR_037435
    Natural varianti901 – 9011Y → S in ARHR2; loss of activity. 1 Publication
    Corresponds to variant rs121908249 [ dbSNP | Ensembl ].
    VAR_063720

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    M57736 mRNA. Translation: AAA63237.1. Different initiation.
    D12485 mRNA. Translation: BAA02054.1. Different initiation.
    AF110304
    , AF110280, AF110281, AF110283, AF110284, AF110285, AF110286, AF110287, AF110288, AF110289, AF110290, AF110291, AF110292, AF110293, AF110294, AF110295, AF110296, AF110297, AF110298, AF110299, AF110300, AF110301, AF110302, AF110303 Genomic DNA. Translation: AAF36094.1.
    AJ242020
    , AJ242021, AJ242022, AJ242023, AJ242024, AJ242025, AJ242026, AJ242027, AJ242028, AJ242029, AJ242030, AJ242031, AJ242032, AJ242033, AJ242034, AJ242035, AJ242036, AJ242037, AJ242038, AJ242039, AJ242040, AJ242041, AJ242042, AJ242043, AJ242044 Genomic DNA. Translation: CAC39442.1.
    AL117378, AL139805 Genomic DNA. Translation: CAI19514.1.
    AL139805, AL117378 Genomic DNA. Translation: CAI20161.1.
    BC059375 mRNA. Translation: AAH59375.2. Different initiation.
    AF067177 Genomic DNA. Translation: AAD38420.1.
    AF067178 Genomic DNA. Translation: AAD38421.1.
    CCDSiCCDS5150.2.
    PIRiA39216.
    RefSeqiNP_006199.2. NM_006208.2.
    UniGeneiHs.527295.

    Genome annotation databases

    EnsembliENST00000360971; ENSP00000354238; ENSG00000197594.
    GeneIDi5167.
    KEGGihsa:5167.
    UCSCiuc011ecf.2. human.

    Polymorphism databases

    DMDMi23503088.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    M57736 mRNA. Translation: AAA63237.1 . Different initiation.
    D12485 mRNA. Translation: BAA02054.1 . Different initiation.
    AF110304
    , AF110280 , AF110281 , AF110283 , AF110284 , AF110285 , AF110286 , AF110287 , AF110288 , AF110289 , AF110290 , AF110291 , AF110292 , AF110293 , AF110294 , AF110295 , AF110296 , AF110297 , AF110298 , AF110299 , AF110300 , AF110301 , AF110302 , AF110303 Genomic DNA. Translation: AAF36094.1 .
    AJ242020
    , AJ242021 , AJ242022 , AJ242023 , AJ242024 , AJ242025 , AJ242026 , AJ242027 , AJ242028 , AJ242029 , AJ242030 , AJ242031 , AJ242032 , AJ242033 , AJ242034 , AJ242035 , AJ242036 , AJ242037 , AJ242038 , AJ242039 , AJ242040 , AJ242041 , AJ242042 , AJ242043 , AJ242044 Genomic DNA. Translation: CAC39442.1 .
    AL117378 , AL139805 Genomic DNA. Translation: CAI19514.1 .
    AL139805 , AL117378 Genomic DNA. Translation: CAI20161.1 .
    BC059375 mRNA. Translation: AAH59375.2 . Different initiation.
    AF067177 Genomic DNA. Translation: AAD38420.1 .
    AF067178 Genomic DNA. Translation: AAD38421.1 .
    CCDSi CCDS5150.2.
    PIRi A39216.
    RefSeqi NP_006199.2. NM_006208.2.
    UniGenei Hs.527295.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2YS0 NMR - A 147-189 [» ]
    ProteinModelPortali P22413.
    SMRi P22413. Positions 106-922.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 111193. 3 interactions.
    IntActi P22413. 3 interactions.
    STRINGi 9606.ENSP00000354238.

    Chemistry

    BindingDBi P22413.
    ChEMBLi CHEMBL5925.
    DrugBanki DB01143. Amifostine.
    DB00811. Ribavirin.

    PTM databases

    PhosphoSitei P22413.

    Polymorphism databases

    DMDMi 23503088.

    Proteomic databases

    MaxQBi P22413.
    PaxDbi P22413.
    PRIDEi P22413.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000360971 ; ENSP00000354238 ; ENSG00000197594 .
    GeneIDi 5167.
    KEGGi hsa:5167.
    UCSCi uc011ecf.2. human.

    Organism-specific databases

    CTDi 5167.
    GeneCardsi GC06P132129.
    HGNCi HGNC:3356. ENPP1.
    HPAi CAB032904.
    MIMi 125853. phenotype.
    173335. gene.
    208000. phenotype.
    602475. phenotype.
    613312. phenotype.
    615522. phenotype.
    neXtProti NX_P22413.
    Orphaneti 289176. Autosomal recessive hypophosphatemic rickets.
    51608. Generalized arterial calcification of infancy.
    324561. Hypopigmentation-punctate palmoplantar keratoderma syndrome.
    PharmGKBi PA27791.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG1524.
    HOGENOMi HOG000037439.
    HOVERGENi HBG051484.
    InParanoidi P22413.
    KOi K01513.
    OMAi FEERILA.
    OrthoDBi EOG7XM2X4.
    PhylomeDBi P22413.
    TreeFami TF330032.

    Enzyme and pathway databases

    Reactomei REACT_11070. Vitamin B2 (riboflavin) metabolism.
    SABIO-RK P22413.

    Miscellaneous databases

    EvolutionaryTracei P22413.
    GeneWikii Ectonucleotide_pyrophosphatase/phosphodiesterase_1.
    GenomeRNAii 5167.
    NextBioi 19990.
    PROi P22413.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P22413.
    Bgeei P22413.
    CleanExi HS_ENPP1.
    Genevestigatori P22413.

    Family and domain databases

    Gene3Di 3.40.570.10. 1 hit.
    3.40.720.10. 1 hit.
    InterProi IPR017849. Alkaline_Pase-like_a/b/a.
    IPR017850. Alkaline_phosphatase_core.
    IPR001604. DNA/RNA_non-sp_Endonuclease.
    IPR024873. E-NPP.
    IPR020821. Extracellular_endonuc_su_A.
    IPR002591. Phosphodiest/P_Trfase.
    IPR020436. Somatomedin_B_chordata.
    IPR001212. Somatomedin_B_dom.
    [Graphical view ]
    PANTHERi PTHR10151. PTHR10151. 1 hit.
    Pfami PF01223. Endonuclease_NS. 1 hit.
    PF01663. Phosphodiest. 1 hit.
    PF01033. Somatomedin_B. 2 hits.
    [Graphical view ]
    PRINTSi PR00022. SOMATOMEDINB.
    SMARTi SM00892. Endonuclease_NS. 1 hit.
    SM00477. NUC. 1 hit.
    SM00201. SO. 2 hits.
    [Graphical view ]
    SUPFAMi SSF53649. SSF53649. 1 hit.
    PROSITEi PS00524. SMB_1. 2 hits.
    PS50958. SMB_2. 2 hits.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Plasma cell membrane glycoprotein PC-1. cDNA cloning of the human molecule, amino acid sequence, and chromosomal location."
      Buckley M.F., Loveland K.A., McKinstry W.J., Garson O.M., Goding J.W.
      J. Biol. Chem. 265:17506-17511(1990) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Skin fibroblast.
    2. Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
      Tissue: Skin fibroblast.
    3. "Genomic structure of the human PC1 gene."
      Bozzali M., Pizzuti A., Trischitta E.
      Submitted (APR-1999) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    4. "The DNA sequence and analysis of human chromosome 6."
      Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D.
      , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.
      Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    5. "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].
      Tissue: Placenta.
    6. "A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance."
      Pizzuti A., Frittitta L., Argiolas A., Baratta R., Goldfine I.D., Bozzali M., Ercolino T., Scarlato G., Iacoviello L., Vigneri R., Tassi V., Trischitta V.
      Diabetes 48:1881-1884(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 145-185, VARIANT GLN-173.
    7. "Biochemical characterization of human PC-1, an enzyme possessing alkaline phosphodiesterase I and nucleotide pyrophosphatase activities."
      Belli S.I., Goding J.W.
      Eur. J. Biochem. 226:433-443(1994) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, TOPOLOGY, CATALYTIC ACTIVITY, FUNCTION, GLYCOSYLATION.
    8. "Autophosphorylation of PC-1 (alkaline phosphodiesterase I/nucleotide pyrophosphatase) and analysis of the active site."
      Belli S.I., Mercuri F.A., Sali A., Goding J.W.
      Eur. J. Biochem. 228:669-676(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACTIVE SITE.
    9. "Molecular cloning and chromosomal localization of PD-Ibeta (PDNP3), a new member of the human phosphodiesterase I genes."
      Piao J.-H., Goding J.W., Nakamura H., Sano K.
      Genomics 45:412-415(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY.
    10. "Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit."
      Maddux B.A., Goldfine I.D.
      Diabetes 49:13-19(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH INSR, FUNCTION IN INHIBITION OF INSR KINASE ACTIVITY.
    11. "Characterization of a di-leucine-based signal in the cytoplasmic tail of the nucleotide-pyrophosphatase NPP1 that mediates basolateral targeting but not endocytosis."
      Bello V., Goding J.W., Greengrass V., Sali A., Dubljevic V., Lenoir C., Trugnan G., Maurice M.
      Mol. Biol. Cell 12:3004-3015(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHARACTERIZATION, SUBCELLULAR LOCATION.
    12. "Expression and localization of ecto-nucleotide pyrophosphatase/phosphodiesterase I-1 (E-NPP1/PC-1) and -3 (E-NPP3/CD203c/PD-Ibeta/B10/gp130(RB13-6)) in inflammatory and neoplastic bile duct diseases."
      Yano Y., Hayashi Y., Sano K., Nagano H., Nakaji M., Seo Y., Ninomiya T., Yoon S., Yokozaki H., Kasuga M.
      Cancer Lett. 207:139-147(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION.
    13. "Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry."
      Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.
      J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-341.
      Tissue: Liver.
    14. "Mass-spectrometric identification and relative quantification of N-linked cell surface glycoproteins."
      Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., Schiess R., Aebersold R., Watts J.D.
      Nat. Biotechnol. 27:378-386(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-341; ASN-643 AND ASN-748.
      Tissue: Leukemic T-cell.
    15. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    16. "Solution structure of the somatomedin B domain of human ectonucleotide pyrophosphatase/phosphodiesterase family member."
      RIKEN structural genomics initiative (RSGI)
      Submitted (OCT-2007) to the PDB data bank
      Cited for: STRUCTURE BY NMR OF 147-189.
    17. "Association of the human NPPS gene with ossification of the posterior longitudinal ligament of the spine (OPLL)."
      Nakamura I., Ikegawa S., Okawa A., Okuda S., Koshizuka Y., Kawaguchi H., Nakamura K., Koyama T., Goto S., Toguchida J., Matsushita M., Ochi T., Takaoka K., Nakamura Y.
      Hum. Genet. 104:492-497(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS OPLL PRO-91 AND PHE-287, VARIANTS GLN-173; HIS-268 AND PRO-779.
    18. Cited for: VARIANTS GACI1 PHE-579 AND CYS-774.
    19. "Generalized arterial calcification of infancy: different clinical courses in two affected siblings."
      Cheng K.-S., Chen M.-R., Ruf N., Lin S.-P., Rutsch F.
      Am. J. Med. Genet. A 136:210-213(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GACI1 VAL-342 AND PHE-371.
    20. "The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin resistance/atherogenic phenotypes, including earlier onset of type 2 diabetes and myocardial infarction."
      Bacci S., Ludovico O., Prudente S., Zhang Y.Y., Di Paola R., Mangiacotti D., Rauseo A., Nolan D., Duffy J., Fini G., Salvemini L., Amico C., Vigna C., Pellegrini F., Menzaghi C., Doria A., Trischitta V.
      Diabetes 54:3021-3025(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT GLN-173, ASSOCIATION WITH NIDDM.
    21. "The mutational spectrum oENPP1 as arising after the analysis of 23 unrelated patients with generalized arterial calcification of infancy (GACI)."
      Ruf N., Uhlenberg B., Terkeltaub R., Nurnberg P., Rutsch F.
      Hum. Mutat. 25:98-98(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS GACI1 LEU-250; TYR-252 DEL; THR-305; VAL-342; PHE-371 AND CYS-774.
    22. "Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets."
      Lorenz-Depiereux B., Schnabel D., Tiosano D., Hausler G., Strom T.M.
      Am. J. Hum. Genet. 86:267-272(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT ARHR2 VAL-266.
    23. "Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene."
      Levy-Litan V., Hershkovitz E., Avizov L., Leventhal N., Bercovich D., Chalifa-Caspi V., Manor E., Buriakovsky S., Hadad Y., Goding J., Parvari R.
      Am. J. Hum. Genet. 86:273-278(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT ARHR2 SER-901, CHARACTERIZATION OF VARIANT ARHR2 SER-901.
    24. "An unusual severe vascular case of pseudoxanthoma elasticum presenting as generalized arterial calcification of infancy."
      Le Boulanger G., Labreze C., Croue A., Schurgers L.J., Chassaing N., Wittkampf T., Rutsch F., Martin L.
      Am. J. Med. Genet. A 152:118-123(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT GLN-173.
    25. Cited for: VARIANTS GACI1 HIS-538 AND ARG-586.
    26. Cited for: VARIANTS COLED SER-149; SER-164 AND TYR-177.

    Entry informationi

    Entry nameiENPP1_HUMAN
    AccessioniPrimary (citable) accession number: P22413
    Secondary accession number(s): Q5T9R6
    , Q9NPZ3, Q9P1P6, Q9UP61, Q9Y6K3
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: August 1, 1991
    Last sequence update: September 19, 2002
    Last modified: October 1, 2014
    This is version 164 of the entry and version 2 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

    Caution

    It is uncertain whether Met-1 or Met-53 is the initiator.Curated

    Keywords - Technical termi

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

    Documents

    1. Human cell differentiation molecules
      CD nomenclature of surface proteins of human leucocytes and list of entries
    2. Human chromosome 6
      Human chromosome 6: entries, gene names and cross-references to MIM
    3. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    4. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    5. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    6. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    7. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3