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Protein

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1

Gene

Enpp1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Appears to modulate insulin sensitivity (By similarity). 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.By similarity2 Publications

Caution

It is uncertain whether Met-1 or Met-35 is the initiator.Curated

Catalytic activityi

Hydrolytically removes 5'-nucleotides successively from the 3'-hydroxy termini of 3'-hydroxy-terminated oligonucleotides.4 Publications
A nucleoside triphosphate + H2O = a nucleotide + diphosphate.4 Publications

Cofactori

Zn2+2 PublicationsNote: Binds 2 Zn2+ ions per subunit.2 Publications

Activity regulationi

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

Kineticsi

  1. KM=46 µM for ATP1 Publication
  2. KM=4.3 mM for UTP1 Publication
  3. KM=4.2 mM for GTP1 Publication
  4. KM=1.2 mM for CTP1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi200Zinc 1; catalytic1 Publication1
    Active sitei238AMP-threonine intermediate1 Publication1
    Metal bindingi238Zinc 1; catalytic1 Publication1
    Binding sitei259Substrate1
    Binding sitei277Substrate1
    Binding sitei322Substrate1
    Metal bindingi358Zinc 2; catalytic1 Publication1
    Metal bindingi362Zinc 2; via tele nitrogen; catalytic1 Publication1
    Metal bindingi405Zinc 1; catalytic1 Publication1
    Metal bindingi406Zinc 1; via tele nitrogen; catalytic1 Publication1
    Metal bindingi517Zinc 2; via tele nitrogen; catalytic1 Publication1
    Metal bindingi781Calcium1 Publication1
    Metal bindingi783Calcium1 Publication1
    Metal bindingi785Calcium1 Publication1
    Metal bindingi787Calcium; via carbonyl oxygen1 Publication1
    Metal bindingi789Calcium1 Publication1
    Sitei896Essential for catalytic activityBy similarity1

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionHydrolase
    Biological processBiomineralization
    LigandCalcium, Metal-binding, Zinc

    Enzyme and pathway databases

    BRENDAi3.1.4.1 3474
    3.6.1.9 3474
    SABIO-RKiP06802

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Ectonucleotide pyrophosphatase/phosphodiesterase family member 1
    Short name:
    E-NPP 1
    Alternative name(s):
    Lymphocyte antigen 41
    Short name:
    Ly-41
    Phosphodiesterase I/nucleotide pyrophosphatase 1
    Plasma-cell membrane glycoprotein PC-1
    Including the following 2 domains:
    Alkaline phosphodiesterase I (EC:3.1.4.14 Publications)
    Nucleotide pyrophosphatase (EC:3.6.1.94 Publications)
    Short name:
    NPPase
    Alternative name(s):
    Nucleotide diphosphataseCurated
    Gene namesi
    Name:Enpp1
    Synonyms:Npps, Pc1, Pdnp1
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
    Proteomesi
    • UP000000589 Componenti: Unplaced

    Organism-specific databases

    MGIiMGI:97370 Enpp1

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Topology

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Topological domaini1 – 58CytoplasmicSequence analysisAdd BLAST58
    Transmembranei59 – 79Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST21
    Topological domaini80 – 906ExtracellularSequence analysisAdd BLAST827

    Keywords - Cellular componenti

    Cell membrane, Membrane, Secreted

    Pathology & Biotechi

    Involvement in diseasei

    Defects in Enpp1 are the cause of the tiptoe walking (ttw) phenotype. Ttw mice exhibit ossification of the spinal ligaments.1 Publication

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi28A → G: No effect on basolateral sorting in epithelial cells. 1 Publication1
    Mutagenesisi30S → A or D: Little change in baolateral sorting in epithelial cells. 1 Publication1
    Mutagenesisi31L → A: 60% of ENPP1 redirected to apical surface in epithelial cells. 75% of ENPP1 redirected to apical surface in epithelial cells; abrogation of increased NPP activity in oestoblastic matrix vesicles; when associated with A-32. 2 Publications1
    Mutagenesisi32L → A: 70% of ENPP1 redirected to apical surface in epithelial cells; abrogation of increased NPP activity in oestoblastic matrix vesicles. 75% of ENPP1 redirected to apical surface in epithelial cells; abrogation of increased NPP activity in oestoblastic matrix vesicles; when associated with A-31. 2 Publications1
    Mutagenesisi42L → A: No change in increased NPP activity in oestoblastic matrix vesicles. 1 Publication1
    Mutagenesisi57Y → G: No change in increased NPP activity in oestoblastic matrix vesicles. 1 Publication1
    Mutagenesisi200D → N: Decreases phosphodiesterase activity by 95%. Abolishes formation of nucleotidylated intermediate. 1 Publication1
    Mutagenesisi237K → A: Decreases phosphodiesterase activity by 40%. Decreased formation of nucleotidylated intermediate. 1 Publication1
    Mutagenesisi238T → A: Abolishes all phosphodiesterase activity. Abolishes formation of nucleotidylated intermediate. 1 Publication1
    Mutagenesisi238T → S: Decreases phosphodiesterase activity by 95%. Accumulates nucleotidylated intermediate. 1 Publication1
    Mutagenesisi239F → A: Decreases phosphodiesterase activity by 50%. Decreased formation of nucleotidylated intermediate. 2 Publications1
    Mutagenesisi242H → L: Strongly decreased phosphodiesterase activity. 1 Publication1
    Mutagenesisi304 – 323Missing : Nearly abolishes activity with nucleotide phosphates. Confers very low activity with lysophospholipids. 1 PublicationAdd BLAST20
    Mutagenesisi308D → A: Decreased phosphodiesterase activity. 1 Publication1
    Mutagenesisi322Y → A: Strongly decreased phosphodiesterase activity. 1 Publication1
    Mutagenesisi358D → Q: Decreases phosphodiesterase activity by 90%. Accumulates nucleotidylated intermediate. 1 Publication1
    Mutagenesisi362H → Q: Decreases phosphodiesterase activity by 95%. 65% activity can be restored by addition of Zn(2+) ions. Accumulates nucleotidylated intermediate. 1 Publication1
    Mutagenesisi405D → N: Abolishes all phosphodiesterase activity. 10% activity can be restored by addition of Zn(2+) ions. Abolishes formation of nucleotidylated intermediate. 1 Publication1
    Mutagenesisi406H → Q: Abolishes all phosphodiesterase activity. 15% activity can be restored by addition of Zn(2+) ions. Abolishes formation of nucleotidylated intermediate. 1 Publication1
    Mutagenesisi517H → Q: Abolishes all phosphodiesterase activity. 60% activity can be restored by addition of Zn(2+) ions. Abolishes formation of nucleotidylated intermediate. 1 Publication1

    Keywords - Diseasei

    Disease mutation

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00001885651 – 906Ectonucleotide pyrophosphatase/phosphodiesterase family member 1Add BLAST906

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei25PhosphoserineBy similarity1
    Disulfide bondi90 ↔ 104PROSITE-ProRule annotation
    Disulfide bondi94 ↔ 122PROSITE-ProRule annotation
    Disulfide bondi102 ↔ 115PROSITE-ProRule annotation
    Disulfide bondi108 ↔ 114PROSITE-ProRule annotation
    Disulfide bondi131 ↔ 148PROSITE-ProRule annotation
    Disulfide bondi136 ↔ 166PROSITE-ProRule annotation
    Disulfide bondi146 ↔ 159PROSITE-ProRule annotation
    Disulfide bondi152 ↔ 158PROSITE-ProRule annotation
    Glycosylationi161N-linked (GlcNAc...) asparagineSequence analysis1
    Disulfide bondi177 ↔ 223
    Disulfide bondi185 ↔ 397
    Modified residuei238PhosphothreonineBy similarity1
    Glycosylationi267N-linked (GlcNAc...) asparagine2 Publications1
    Glycosylationi323N-linked (GlcNAc...) asparagine3 Publications1
    Disulfide bondi413 ↔ 512
    Glycosylationi459N-linked (GlcNAc...) asparagine1 Publication1
    Disulfide bondi462 ↔ 849
    Glycosylationi567N-linked (GlcNAc...) asparagine2 Publications1
    Disulfide bondi596 ↔ 653
    Disulfide bondi607 ↔ 707
    Disulfide bondi609 ↔ 692
    Glycosylationi624N-linked (GlcNAc...) asparagine2 Publications1
    Disulfide bondi819 ↔ 829

    Post-translational modificationi

    The N-terminal is blocked.
    N-glycosylated.5 Publications
    A secreted form is produced through cleavage at Lys-85 by intracellular processing.

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sitei84 – 85Cleavage2

    Keywords - PTMi

    Disulfide bond, Glycoprotein, Phosphoprotein

    Proteomic databases

    MaxQBiP06802
    PaxDbiP06802
    PRIDEiP06802

    PTM databases

    iPTMnetiP06802
    PhosphoSitePlusiP06802
    SwissPalmiP06802

    Expressioni

    Tissue specificityi

    Selectively expressed on the surface of antibody-secreting cells.

    Interactioni

    Subunit structurei

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

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    itself2EBI-16016057,EBI-16016057

    GO - Molecular functioni

    Protein-protein interaction databases

    DIPiDIP-59981N
    STRINGi10090.ENSMUSP00000101159

    Structurei

    Secondary structure

    1906
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliP06802
    SMRiP06802
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini86 – 126SMB 1PROSITE-ProRule annotationAdd BLAST41
    Domaini127 – 171SMB 2PROSITE-ProRule annotationAdd BLAST45

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni173 – 573PhosphodiesteraseAdd BLAST401
    Regioni579 – 628LinkerAdd BLAST50
    Regioni635 – 906NucleaseAdd BLAST272

    Motif

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Motifi27 – 34Di-leucine motif8

    Domaini

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

    Sequence similaritiesi

    Keywords - Domaini

    Repeat, Signal-anchor, Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiKOG2645 Eukaryota
    COG1524 LUCA
    HOGENOMiHOG000034646
    HOVERGENiHBG051484
    InParanoidiP06802
    KOiK01513
    PhylomeDBiP06802

    Family and domain databases

    Gene3Di3.40.720.10, 1 hit
    InterProiView protein in InterPro
    IPR017849 Alkaline_Pase-like_a/b/a
    IPR017850 Alkaline_phosphatase_core_sf
    IPR001604 DNA/RNA_non-sp_Endonuclease
    IPR020821 Extracellular_endonuc_su_A
    IPR002591 Phosphodiest/P_Trfase
    IPR036024 Somatomedin_B-like_dom_sf
    IPR020436 Somatomedin_B_chordata
    IPR001212 Somatomedin_B_dom
    PfamiView protein in Pfam
    PF01223 Endonuclease_NS, 1 hit
    PF01663 Phosphodiest, 1 hit
    PF01033 Somatomedin_B, 2 hits
    PRINTSiPR00022 SOMATOMEDINB
    SMARTiView protein in SMART
    SM00892 Endonuclease_NS, 1 hit
    SM00477 NUC, 1 hit
    SM00201 SO, 2 hits
    SUPFAMiSSF53649 SSF53649, 1 hit
    SSF90188 SSF90188, 2 hits
    PROSITEiView protein in PROSITE
    PS00524 SMB_1, 2 hits
    PS50958 SMB_2, 2 hits

    Sequences (2+)i

    Sequence statusi: Complete.

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

    This entry has 2 described isoforms and 3 potential isoforms that are computationally mapped.Show allAlign All

    Isoform 2 (identifier: P06802-1) [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
    MERDGDQAGH GPRHGSAGNG RELESPAAAS LLAPMDLGEE PLEKAERARP
    60 70 80 90 100
    AKDPNTYKVL SLVLSVCVLT TILGCIFGLK PSCAKEVKSC KGRCFERTFS
    110 120 130 140 150
    NCRCDAACVS LGNCCLDFQE TCVEPTHIWT CNKFRCGEKR LSRFVCSCAD
    160 170 180 190 200
    DCKTHNDCCI NYSSVCQDKK SWVEETCESI DTPECPAEFE SPPTLLFSLD
    210 220 230 240 250
    GFRAEYLHTW GGLLPVISKL KNCGTYTKNM RPMYPTKTFP NHYSIVTGLY
    260 270 280 290 300
    PESHGIIDNK MYDPKMNASF SLKSKEKFNP LWYKGQPIWV TANHQEVKSG
    310 320 330 340 350
    TYFWPGSDVE IDGILPDIYK VYNGSVPFEE RILAVLEWLQ LPSHERPHFY
    360 370 380 390 400
    TLYLEEPDSS GHSHGPVSSE VIKALQKVDR LVGMLMDGLK DLGLDKCLNL
    410 420 430 440 450
    ILISDHGMEQ GSCKKYVYLN KYLGDVNNVK VVYGPAARLR PTDVPETYYS
    460 470 480 490 500
    FNYEALAKNL SCREPNQHFR PYLKPFLPKR LHFAKSDRIE PLTFYLDPQW
    510 520 530 540 550
    QLALNPSERK YCGSGFHGSD NLFSNMQALF IGYGPAFKHG AEVDSFENIE
    560 570 580 590 600
    VYNLMCDLLG LIPAPNNGSH GSLNHLLKKP IYNPSHPKEE GFLSQCPIKS
    610 620 630 640 650
    TSNDLGCTCD PWIVPIKDFE KQLNLTTEDV DDIYHMTVPY GRPRILLKQH
    660 670 680 690 700
    HVCLLQQQQF LTGYSLDLLM PLWASYTFLR NDQFSRDDFS NCLYQDLRIP
    710 720 730 740 750
    LSPVHKCSYY KSNSKLSYGF LTPPRLNRVS NHIYSEALLT SNIVPMYQSF
    760 770 780 790 800
    QVIWHYLHDT LLQRYAHERN GINVVSGPVF DFDYDGRYDS LEILKQNSRV
    810 820 830 840 850
    IRSQEILIPT HFFIVLTSCK QLSETPLECS ALESSAYILP HRPDNIESCT
    860 870 880 890 900
    HGKRESSWVE ELLTLHRARV TDVELITGLS FYQDRQESVS ELLRLKTHLP

    IFSQED
    Length:906
    Mass (Da):103,176
    Last modified:September 19, 2002 - v4
    Checksum:i068D45B0ED0F224D
    GO
    Isoform 1 (identifier: P06802-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         630-630: Missing.

    Show »
    Length:905
    Mass (Da):103,076
    Checksum:iFB6EEEA0FF659421
    GO

    Computationally mapped potential isoform sequencesi

    There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    A0A0R4J1Q7A0A0R4J1Q7_MOUSE
    Ectonucleotide pyrophosphatase/phos...
    Enpp1 mCG_9001
    906Annotation score:
    G3X9S2G3X9S2_MOUSE
    Ectonucleotide pyrophosphatase/phos...
    Enpp1 mCG_9001
    905Annotation score:
    E9QQ26E9QQ26_MOUSE
    Ectonucleotide pyrophosphatase/phos...
    Enpp1
    369Annotation score:

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural varianti651H → R in allele ENPP1b. 1 Publication1
    Natural varianti680R → S in allele ENPP1b. 1 Publication1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_006748630Missing in isoform 1. 2 Publications1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    J02700 mRNA Translation: AAA39893.2
    AF339910 mRNA Translation: AAK84174.1
    AK088857 mRNA Translation: BAC40616.1
    L04516 Unassigned DNA No translation available.
    M12552 mRNA Translation: AAA39892.1
    CCDSiCCDS35870.1 [P06802-2]
    CCDS78802.1 [P06802-1]
    PIRiA27410
    RefSeqiNP_001295256.1, NM_001308327.1
    UniGeneiMm.27254
    Mm.478860

    Genome annotation databases

    GeneIDi18605
    KEGGimmu:18605

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    J02700 mRNA Translation: AAA39893.2
    AF339910 mRNA Translation: AAK84174.1
    AK088857 mRNA Translation: BAC40616.1
    L04516 Unassigned DNA No translation available.
    M12552 mRNA Translation: AAA39892.1
    CCDSiCCDS35870.1 [P06802-2]
    CCDS78802.1 [P06802-1]
    PIRiA27410
    RefSeqiNP_001295256.1, NM_001308327.1
    UniGeneiMm.27254
    Mm.478860

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    4B56X-ray3.00A/B87-906[»]
    4GTWX-ray2.70A/B92-906[»]
    4GTXX-ray3.20A/B92-906[»]
    4GTYX-ray3.19A/B92-906[»]
    4GTZX-ray3.19A/B92-906[»]
    ProteinModelPortaliP06802
    SMRiP06802
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    DIPiDIP-59981N
    STRINGi10090.ENSMUSP00000101159

    PTM databases

    iPTMnetiP06802
    PhosphoSitePlusiP06802
    SwissPalmiP06802

    Proteomic databases

    MaxQBiP06802
    PaxDbiP06802
    PRIDEiP06802

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    GeneIDi18605
    KEGGimmu:18605

    Organism-specific databases

    CTDi5167
    MGIiMGI:97370 Enpp1

    Phylogenomic databases

    eggNOGiKOG2645 Eukaryota
    COG1524 LUCA
    HOGENOMiHOG000034646
    HOVERGENiHBG051484
    InParanoidiP06802
    KOiK01513
    PhylomeDBiP06802

    Enzyme and pathway databases

    BRENDAi3.1.4.1 3474
    3.6.1.9 3474
    SABIO-RKiP06802

    Miscellaneous databases

    ChiTaRSiEnpp1 mouse
    PROiPR:P06802
    SOURCEiSearch...

    Family and domain databases

    Gene3Di3.40.720.10, 1 hit
    InterProiView protein in InterPro
    IPR017849 Alkaline_Pase-like_a/b/a
    IPR017850 Alkaline_phosphatase_core_sf
    IPR001604 DNA/RNA_non-sp_Endonuclease
    IPR020821 Extracellular_endonuc_su_A
    IPR002591 Phosphodiest/P_Trfase
    IPR036024 Somatomedin_B-like_dom_sf
    IPR020436 Somatomedin_B_chordata
    IPR001212 Somatomedin_B_dom
    PfamiView protein in Pfam
    PF01223 Endonuclease_NS, 1 hit
    PF01663 Phosphodiest, 1 hit
    PF01033 Somatomedin_B, 2 hits
    PRINTSiPR00022 SOMATOMEDINB
    SMARTiView protein in SMART
    SM00892 Endonuclease_NS, 1 hit
    SM00477 NUC, 1 hit
    SM00201 SO, 2 hits
    SUPFAMiSSF53649 SSF53649, 1 hit
    SSF90188 SSF90188, 2 hits
    PROSITEiView protein in PROSITE
    PS00524 SMB_1, 2 hits
    PS50958 SMB_2, 2 hits
    ProtoNetiSearch...

    Entry informationi

    Entry nameiENPP1_MOUSE
    AccessioniPrimary (citable) accession number: P06802
    Secondary accession number(s): Q542E9, Q924C4
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 1, 1988
    Last sequence update: September 19, 2002
    Last modified: November 7, 2018
    This is version 184 of the entry and version 4 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

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

    Documents

    1. SIMILARITY comments
      Index of protein domains and families
    2. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    UniProt is an ELIXIR core data resource
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