Reviewed,
UniProtKB/Swiss-Prot P22413 (ENPP1_HUMAN)
Last modified
November 3, 2009.
Version 111.
History...
Clusters with 100%,
90%,
50% identity |
Documents (7) |
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Names and origin
| Protein names | Recommended name: Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 Short name=E-NPP 1 Alternative name(s): Phosphodiesterase I/nucleotide pyrophosphatase 1 Plasma-cell membrane glycoprotein PC-1 Including the following 2 domains: 1- Recommended name: Alkaline phosphodiesterase I EC=3.1.4.1 2- Recommended name: Nucleotide pyrophosphatase Short name=NPPase EC=3.6.1.9 | ||||
| Gene names |
| ||||
| Organism | Homo sapiens (Human) [Complete proteome] | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 925 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is not processed. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | Involved primarily in ATP hydrolysis at the plasma membrane. Plays a role in regulating pyrophosphate levels, and functions in bone mineralization and soft tissue calcification. In vitro, has a broad specificity, hydrolyzing 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. |
| Catalytic activity | Hydrolytically removes 5'-nucleotides successively from the 3'-hydroxy termini of 3'-hydroxy-terminated oligonucleotides. A dinucleotide + H2O = 2 mononucleotides. |
| Cofactor | Binds 2 divalent metal cations per subunit Probable. |
| Enzyme regulation | At low concentrations of ATP, a phosphorylated intermediate is formed which inhibits further hydrolysis. |
| Subunit structure | Homodimer; disulfide-linked. |
| Subcellular location | Membrane; Single-pass type II membrane protein. Basolateral cell membrane; Single-pass type II membrane protein. Note: 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. Ref.10 Ref.11 |
| Tissue specificity | Expressed in plasma cells and also in a number of non-lymphoid tissues, including the distal convoluted tubule of the kidney, chondrocytes and epididymis. Ref.9 |
| Domain | The di-leucine motif is required for basolateral targeting in epithelial cells, and for targeting to matrix vesicles derived from mineralizing cells By similarity. |
| Post-translational modification | Autophosphorylated as part of the catalytic cycle of phosphodiesterase/pyrophosphatase activity. It has been suggested that the active SMB domain may be permitted considerable disulfide bond heterogeneity or variability, thus two alternate disulfide patterns based on 3D structures are described with 1 disulfide bond conserved in both. |
| Involvement in disease | Defects in ENPP1 are a cause of increased susceptibility for ossification of the posterior longitudinal ligament of the spine (OPLL) [MIM:602475]. OPLL is a common form of human myelopathy with a prevalence of as much as 4% in a variety of ethnic groups. Ref.15 Defects in ENPP1 are a cause of idiopathic infantile arterial calcification (IIAC) [MIM:208000]; also known as generalized arterial calcification of infancy. IIAC is characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. Ref.16 Ref.17 Defects in ENPP1 are associated with obesity, glucose intolerance, and type II diabetes non-insulin dependent (NIDDM) [MIM:125853]. Ref.18 |
| Sequence similarities | Belongs to the nucleotide pyrophosphatase/phosphodiesterase family. Contains 2 SMB (somatomedin-B) domains. |
| Caution | It is uncertain whether Met-1 or Met-53 is the initiator. |
Ontologies
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||||||||||
Molecule processing | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 925 | 925 | Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 | PRO_0000188564 | |||||||||||||
Regions | |||||||||||||||||
| Topological domain | 1 – 76 | 76 | Cytoplasmic Potential | ||||||||||||||
| Transmembrane | 77 – 97 | 21 | Signal-anchor for type II membrane protein Potential | ||||||||||||||
| Topological domain | 98 – 925 | 828 | Extracellular Potential | ||||||||||||||
| Domain | 104 – 144 | 41 | SMB 1 | ||||||||||||||
| Domain | 145 – 189 | 45 | SMB 2 | ||||||||||||||
| Region | 191 – 591 | 401 | Phosphodiesterase | ||||||||||||||
| Region | 654 – 925 | 272 | Nuclease | ||||||||||||||
| Motif | 45 – 52 | 8 | Di-leucine motif | ||||||||||||||
Sites | |||||||||||||||||
| Active site | 256 | 1 | AMP-threonine intermediate By similarity | ||||||||||||||
| Metal binding | 218 | 1 | Divalent metal cation 2 Probable | ||||||||||||||
| Metal binding | 376 | 1 | Divalent metal cation 1 Probable | ||||||||||||||
| Metal binding | 380 | 1 | Divalent metal cation 1 Probable | ||||||||||||||
| Metal binding | 423 | 1 | Divalent metal cation 2 Probable | ||||||||||||||
| Metal binding | 424 | 1 | Divalent metal cation 2 Probable | ||||||||||||||
| Metal binding | 535 | 1 | Divalent metal cation 1 Probable | ||||||||||||||
| Site | 915 | 1 | Essential for catalytic activity By similarity | ||||||||||||||
Amino acid modifications | |||||||||||||||||
| Glycosylation | 179 | 1 | N-linked (GlcNAc...) Potential | ||||||||||||||
| Glycosylation | 285 | 1 | N-linked (GlcNAc...) Potential | ||||||||||||||
| Glycosylation | 341 | 1 | N-linked (GlcNAc...) Ref.12 Ref.13 | ||||||||||||||
| Glycosylation | 477 | 1 | N-linked (GlcNAc...) Potential | ||||||||||||||
| Glycosylation | 585 | 1 | N-linked (GlcNAc...) Potential | ||||||||||||||
| Glycosylation | 643 | 1 | N-linked (GlcNAc...) Ref.13 | ||||||||||||||
| Glycosylation | 700 | 1 | N-linked (GlcNAc...) Potential | ||||||||||||||
| Glycosylation | 731 | 1 | N-linked (GlcNAc...) Potential | ||||||||||||||
| Glycosylation | 748 | 1 | N-linked (GlcNAc...) Ref.13 | ||||||||||||||
| Disulfide bond | 108 ↔ 122 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 108 ↔ 112 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 112 ↔ 140 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 120 ↔ 133 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 120 ↔ 122 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 126 ↔ 132 | By similarity | |||||||||||||||
| Disulfide bond | 133 ↔ 140 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 149 ↔ 166 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 149 ↔ 154 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 154 ↔ 184 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 164 ↔ 177 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 164 ↔ 166 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 170 ↔ 176 | By similarity | |||||||||||||||
| Disulfide bond | 177 ↔ 184 | Alternate By similarity | |||||||||||||||
| Disulfide bond | 480 ↔ 868 | By similarity | |||||||||||||||
Natural variations | |||||||||||||||||
| Natural variant | 91 | 1 | L → P in OPLL. Ref.15 | VAR_014141 | |||||||||||||
| Natural variant | 173 | 1 | K → Q Associated with NIDDM. dbSNP rs1044498. Ref.15 Ref.18 Ref.6 | VAR_008873 | |||||||||||||
| Natural variant | 179 | 1 | N → S: dbSNP rs2273411. | VAR_037432 | |||||||||||||
| Natural variant | 268 | 1 | Y → H: dbSNP rs1805139. Ref.15 | VAR_014142 | |||||||||||||
| Natural variant | 287 | 1 | S → F in OPLL. Ref.15 | VAR_014143 | |||||||||||||
| Natural variant | 342 | 1 | G → V in IIAC. Ref.17 | VAR_037433 | |||||||||||||
| Natural variant | 371 | 1 | Y → F in IIAC. Ref.17 | VAR_037434 | |||||||||||||
| Natural variant | 579 | 1 | L → F in IIAC. Ref.16 | VAR_018514 | |||||||||||||
| Natural variant | 774 | 1 | R → C in IIAC. dbSNP rs28933977. Ref.16 | VAR_018515 | |||||||||||||
| Natural variant | 779 | 1 | T → P: dbSNP rs1805138. Ref.15 | VAR_014144 | |||||||||||||
| Natural variant | 886 | 1 | R → T: dbSNP rs8192683. | VAR_037435 | |||||||||||||
Secondary structure | |||||||||||||||||
Helix Strand Turn | |||||||||||||||||
| Turn | 151 – 155 | 5 | |||||||||||||||
| Beta strand | 163 – 165 | 3 | |||||||||||||||
| Helix | 168 – 173 | 6 | |||||||||||||||
| Helix | 180 – 183 | 4 | |||||||||||||||
Sequences
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References
| « Hide 'large scale' references | |
| [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: 2211644] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Skin fibroblast. |
| [2] | "Molecular cloning of cDNAs for human fibroblast nucleotide pyrophosphatase." Funakoshi I., Kato H., Horie K., Yano T., Hori Y., Kobayashi H., Inoue T., Suzuki H., Fukui S., Tsukahara M., Kajii T., Yamashina I. Arch. Biochem. Biophys. 295:180-187(1992) [PubMed: 1315502] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. 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. Beck S.Nature 425:805-811(2003) [PubMed: 14574404] [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: 15489334] [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: 10480624] [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: 8001561] [Abstract] Cited for: CHARACTERIZATION. |
| [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: 7737162] [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: 9344668] [Abstract] Cited for: TISSUE SPECIFICITY. |
| [10] | "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: 11598187] [Abstract] Cited for: CHARACTERIZATION, SUBCELLULAR LOCATION. |
| [11] | "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: 15072822] [Abstract] Cited for: SUBCELLULAR LOCATION. |
| [12] | "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: 19159218] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-341, MASS SPECTROMETRY. Tissue: Liver. |
| [13] | "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: 19349973] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-341; ASN-643 AND ASN-748, MASS SPECTROMETRY. |
| [14] | "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. |
| [15] | "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: 10453738] [Abstract] Cited for: VARIANTS OPLL PRO-91 AND PHE-287, VARIANTS GLN-173; HIS-268 AND PRO-779. |
| [16] | "Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification." Rutsch F., Ruf N., Vaingankar S., Toliat M.R., Suk A., Hohne W., Schauer G., Lehmann M., Roscioli T., Schnabel D., Epplen J.T., Knisely A., Superti-Furga A., McGill J., Filippone M., Sinaiko A.R., Vallance H., Hinrichs B. Nuernberg P.Nat. Genet. 34:379-381(2003) [PubMed: 12881724] [Abstract] Cited for: VARIANTS IIAC PHE-579 AND CYS-774. |
| [17] | "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: 15940697] [Abstract] Cited for: VARIANTS IIAC VAL-342 AND PHE-371. |
| [18] | "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: 16186408] [Abstract] Cited for: VARIANT GLN-173, ASSOCIATION WITH OBESITY, GLUCOSE INTOLERANCE AND NIDDM. |
| + | Additional computationally mapped references. |
Cross-references
Sequence databases | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| M57736 mRNA. Translation: AAA63237.1. Different initiation. D12485 mRNA. Translation: BAA02054.1. Different initiation. AF110304 AF110303 Genomic DNA. Translation: AAF36094.1. AJ242020 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. | |||||||||||||
| IPI | IPI00184311. | ||||||||||||
| PIR | A39216. | ||||||||||||
| RefSeq | NP_006199.2. | ||||||||||||
| UniGene | Hs.527295 | ||||||||||||
3D structure databases | |||||||||||||
| |||||||||||||
| ModBase | Search... | ||||||||||||
Protein-protein interaction databases | |||||||||||||
| STRING | P22413. | ||||||||||||
PTM databases | |||||||||||||
| PhosphoSite | P22413. | ||||||||||||
Proteomic databases | |||||||||||||
| PRIDE | P22413. | ||||||||||||
Genome annotation databases | |||||||||||||
| Ensembl | ENST00000358229; ENSP00000350964; ENSG00000197594; Homo sapiens. [Genome view] ENST00000360971; ENSP00000354238; ENSG00000197594; Homo sapiens. [Genome view] | ||||||||||||
| GeneID | 5167. | ||||||||||||
| KEGG | hsa:5167. | ||||||||||||
| UCSC | uc003qcx.2. human. | ||||||||||||
Organism-specific databases | |||||||||||||
| CTD | 5167. | ||||||||||||
| GeneCards | GC06P132170. | ||||||||||||
| H-InvDB | HIX0025075. | ||||||||||||
| HGNC | HGNC:3356. ENPP1. | ||||||||||||
| MIM | 125853. phenotype. 173335. gene. 208000. phenotype. 602475. phenotype. | ||||||||||||
| Orphanet | 51608. Arterial calcification, generalized, of infancy. | ||||||||||||
| PharmGKB | PA27791. | ||||||||||||
| GenAtlas | Search... | ||||||||||||
Phylogenomic databases | |||||||||||||
| HOVERGEN | P22413. | ||||||||||||
| OMA | ERPHFYT. | ||||||||||||
Enzyme and pathway databases | |||||||||||||
| BRENDA | 3.1.4.1. 247. 3.6.1.9. 247. | ||||||||||||
| Reactome | REACT_11193. Metabolism of vitamins and cofactors. | ||||||||||||
Gene expression databases | |||||||||||||
| ArrayExpress | P22413. | ||||||||||||
| Bgee | P22413. | ||||||||||||
| CleanEx | HS_ENPP1. | ||||||||||||
| Genevestigator | P22413. | ||||||||||||
| GermOnline | ENSG00000197594. Homo sapiens. | ||||||||||||
Family and domain databases | |||||||||||||
| InterPro | IPR017849. Alkaline_Pase-like_a/b/a. IPR001604. Endonuclease. IPR002591. Phosphodiest/P_Trfase. IPR001212. Somatomedin_B. IPR020436. Somatomedin_B_chordata. [Graphical view] | ||||||||||||
| Gene3D | G3DSA:3.40.720.10. Alk_phosphtse. 1 hit. G3DSA:3.40.570.10. Endonuclease. 1 hit. | ||||||||||||
| Pfam | PF01663. Phosphodiest. 1 hit. PF01033. Somatomedin_B. 2 hits. [Graphical view] | ||||||||||||
| PRINTS | PR00022. SOMATOMEDINB. | ||||||||||||
| SMART | SM00477. NUC. 1 hit. SM00201. SO. 2 hits. [Graphical view] | ||||||||||||
| PROSITE | PS00524. SMB_1. 2 hits. PS50958. SMB_2. 2 hits. [Graphical view] | ||||||||||||
| ProtoNet | Search... | ||||||||||||
Other Resources | |||||||||||||
| DrugBank | DB01143. Amifostine. DB00811. Ribavirin. | ||||||||||||
| NextBio | 19990. | ||||||||||||
| SOURCE | Search... | ||||||||||||
Entry information
| Entry name | ENPP1_HUMAN | ||||||||
| Accession | Primary (citable) accession number: P22413 Secondary accession number(s): Q5T9R6 Q9Y6K3 | ||||||||
| Entry history |
| ||||||||
| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation project | HPI (Human Proteome Initiative) | ||||||||
| Disclaimer | Any 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. | ||||||||
Relevant documents
| Human cell differentiation molecules CD nomenclature of surface proteins of human leucocytes and list of entries |
| Human chromosome 6 Human chromosome 6: entries, gene names and cross-references to MIM |
| Human entries with polymorphisms or disease mutations List of human entries with polymorphisms or disease mutations |
| Human polymorphisms and disease mutations Index of human polymorphisms and disease mutations |
| MIM cross-references Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot |
| PDB cross-references Index of Protein Data Bank (PDB) cross-references |
| SIMILARITY comments Index of protein domains and families |

Clusters with


