ID ENPP1_HUMAN Reviewed; 925 AA. AC P22413; Q5T9R6; Q9NPZ3; Q9P1P6; Q9UP61; Q9Y6K3; DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot. DT 19-SEP-2002, sequence version 2. DT 27-MAR-2024, entry version 233. DE RecName: Full=Ectonucleotide pyrophosphatase/phosphodiesterase family member 1; DE Short=E-NPP 1 {ECO:0000303|PubMed:15072822}; DE AltName: Full=Membrane component chromosome 6 surface marker 1; DE AltName: Full=Phosphodiesterase I/nucleotide pyrophosphatase 1; DE AltName: Full=Plasma-cell membrane glycoprotein PC-1 {ECO:0000303|PubMed:2211644}; DE Includes: DE RecName: Full=Alkaline phosphodiesterase I {ECO:0000303|PubMed:8001561}; DE EC=3.1.4.1 {ECO:0000269|PubMed:8001561}; DE Includes: DE RecName: Full=Nucleotide pyrophosphatase {ECO:0000303|PubMed:8001561}; DE Short=NPPase; DE EC=3.6.1.9 {ECO:0000269|PubMed:8001561}; DE AltName: Full=Nucleotide diphosphatase {ECO:0000305}; DE Contains: DE RecName: Full=Ectonucleotide pyrophosphatase/phosphodiesterase family member 1, secreted form {ECO:0000305}; GN Name=ENPP1 {ECO:0000312|HGNC:HGNC:3356}; GN Synonyms=M6S1, NPPS {ECO:0000303|PubMed:10453738}, PC1 GN {ECO:0000303|PubMed:2211644}, PDNP1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Skin fibroblast; RX PubMed=2211644; DOI=10.1016/s0021-9258(18)38193-6; RA Buckley M.F., Loveland K.A., McKinstry W.J., Garson O.M., Goding J.W.; RT "Plasma cell membrane glycoprotein PC-1. cDNA cloning of the human RT molecule, amino acid sequence, and chromosomal location."; RL J. Biol. Chem. 265:17506-17511(1990). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE. RC TISSUE=Skin fibroblast; RX PubMed=1315502; DOI=10.1016/0003-9861(92)90504-p; RA Funakoshi I., Kato H., Horie K., Yano T., Hori Y., Kobayashi H., Inoue T., RA Suzuki H., Fukui S., Tsukahara M., Kajii T., Yamashina I.; RT "Molecular cloning of cDNAs for human fibroblast nucleotide RT pyrophosphatase."; RL Arch. Biochem. Biophys. 295:180-187(1992). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Bozzali M., Pizzuti A., Trischitta E.; RT "Genomic structure of the human PC1 gene."; RL Submitted (APR-1999) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 145-185, AND VARIANT GLN-173. RX PubMed=10480624; DOI=10.2337/diabetes.48.9.1881; RA Pizzuti A., Frittitta L., Argiolas A., Baratta R., Goldfine I.D., RA Bozzali M., Ercolino T., Scarlato G., Iacoviello L., Vigneri R., Tassi V., RA Trischitta V.; RT "A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region RT is strongly associated with insulin resistance."; RL Diabetes 48:1881-1884(1999). RN [7] RP SUBCELLULAR LOCATION, TOPOLOGY, CATALYTIC ACTIVITY, FUNCTION, AND RP GLYCOSYLATION. RX PubMed=8001561; DOI=10.1111/j.1432-1033.1994.tb20068.x; RA Belli S.I., Goding J.W.; RT "Biochemical characterization of human PC-1, an enzyme possessing alkaline RT phosphodiesterase I and nucleotide pyrophosphatase activities."; RL Eur. J. Biochem. 226:433-443(1994). RN [8] RP ACTIVE SITE. RX PubMed=7737162; DOI=10.1111/j.1432-1033.1995.tb20308.x; RA Belli S.I., Mercuri F.A., Sali A., Goding J.W.; RT "Autophosphorylation of PC-1 (alkaline phosphodiesterase I/nucleotide RT pyrophosphatase) and analysis of the active site."; RL Eur. J. Biochem. 228:669-676(1995). RN [9] RP TISSUE SPECIFICITY. RX PubMed=9344668; DOI=10.1006/geno.1997.4949; RA Piao J.-H., Goding J.W., Nakamura H., Sano K.; RT "Molecular cloning and chromosomal localization of PD-Ibeta (PDNP3), a new RT member of the human phosphodiesterase I genes."; RL Genomics 45:412-415(1997). RN [10] RP FUNCTION. RX PubMed=11004006; DOI=10.1152/ajpregu.2000.279.4.r1365; RA Johnson K.A., Hessle L., Vaingankar S., Wennberg C., Mauro S., Narisawa S., RA Goding J.W., Sano K., Millan J.L., Terkeltaub R.; RT "Osteoblast tissue-nonspecific alkaline phosphatase antagonizes and RT regulates PC-1."; RL Am. J. Physiol. 279:R1365-R1377(2000). RN [11] RP INTERACTION WITH INSR, AND FUNCTION IN INHIBITION OF INSR KINASE ACTIVITY. RX PubMed=10615944; DOI=10.2337/diabetes.49.1.13; RA Maddux B.A., Goldfine I.D.; RT "Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs RT via direct interaction with the receptor alpha-subunit."; RL Diabetes 49:13-19(2000). RN [12] RP CHARACTERIZATION, AND SUBCELLULAR LOCATION. RX PubMed=11598187; DOI=10.1091/mbc.12.10.3004; RA Bello V., Goding J.W., Greengrass V., Sali A., Dubljevic V., Lenoir C., RA Trugnan G., Maurice M.; RT "Characterization of a di-leucine-based signal in the cytoplasmic tail of RT the nucleotide-pyrophosphatase NPP1 that mediates basolateral targeting but RT not endocytosis."; RL Mol. Biol. Cell 12:3004-3015(2001). RN [13] RP SUBCELLULAR LOCATION. RX PubMed=15072822; DOI=10.1016/j.canlet.2003.11.002; RA Yano Y., Hayashi Y., Sano K., Nagano H., Nakaji M., Seo Y., Ninomiya T., RA Yoon S., Yokozaki H., Kasuga M.; RT "Expression and localization of ecto-nucleotide RT pyrophosphatase/phosphodiesterase I-1 (E-NPP1/PC-1) and -3 (E- RT NPP3/CD203c/PD-Ibeta/B10/gp130(RB13-6)) in inflammatory and neoplastic bile RT duct diseases."; RL Cancer Lett. 207:139-147(2004). RN [14] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-341. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [15] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-341; ASN-643 AND ASN-748. RC TISSUE=Leukemic T-cell; RX PubMed=19349973; DOI=10.1038/nbt.1532; RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., RA Schiess R., Aebersold R., Watts J.D.; RT "Mass-spectrometric identification and relative quantification of N-linked RT cell surface glycoproteins."; RL Nat. Biotechnol. 27:378-386(2009). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [17] RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=25344812; DOI=10.1038/nchembio.1661; RA Li L., Yin Q., Kuss P., Maliga Z., Millan J.L., Wu H., Mitchison T.J.; RT "Hydrolysis of 2'3'-cGAMP by ENPP1 and design of nonhydrolyzable analogs."; RL Nat. Chem. Biol. 10:1043-1048(2014). RN [18] RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=28011303; DOI=10.1016/j.bbagen.2016.12.019; RA Namasivayam V., Lee S.Y., Mueller C.E.; RT "The promiscuous ectonucleotidase NPP1: molecular insights into substrate RT binding and hydrolysis."; RL Biochim. Biophys. Acta 1861:603-614(2017). RN [19] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=35147247; DOI=10.1002/jbmr.4528; RA Szeri F., Niaziorimi F., Donnelly S., Fariha N., Tertyshnaia M., Patel D., RA Lundkvist S., van de Wetering K.; RT "The Mineralization Regulator ANKH Mediates Cellular Efflux of ATP, Not RT Pyrophosphate."; RL J. Bone Miner. Res. 37:1024-1031(2022). RN [20] RP STRUCTURE BY NMR OF 147-189. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the somatomedin B domain of human ectonucleotide RT pyrophosphatase/phosphodiesterase family member."; RL Submitted (OCT-2007) to the PDB data bank. RN [21] RP VARIANTS OPLL PRO-91 AND PHE-287, AND VARIANTS GLN-173; HIS-268 AND RP PRO-779. RX PubMed=10453738; DOI=10.1007/s004390050993; RA Nakamura I., Ikegawa S., Okawa A., Okuda S., Koshizuka Y., Kawaguchi H., RA Nakamura K., Koyama T., Goto S., Toguchida J., Matsushita M., Ochi T., RA Takaoka K., Nakamura Y.; RT "Association of the human NPPS gene with ossification of the posterior RT longitudinal ligament of the spine (OPLL)."; RL Hum. Genet. 104:492-497(1999). RN [22] RP VARIANT GACI1 PHE-579, AND VARIANT CYS-774. RX PubMed=12881724; DOI=10.1038/ng1221; RA Rutsch F., Ruf N., Vaingankar S., Toliat M.R., Suk A., Hohne W., RA Schauer G., Lehmann M., Roscioli T., Schnabel D., Epplen J.T., Knisely A., RA Superti-Furga A., McGill J., Filippone M., Sinaiko A.R., Vallance H., RA Hinrichs B., Smith W., Ferre M., Terkeltaub R., Nuernberg P.; RT "Mutations in ENPP1 are associated with 'idiopathic' infantile arterial RT calcification."; RL Nat. Genet. 34:379-381(2003). RN [23] RP VARIANTS GACI1 VAL-342 AND PHE-371. RX PubMed=15940697; DOI=10.1002/ajmg.a.30800; RA Cheng K.-S., Chen M.-R., Ruf N., Lin S.-P., Rutsch F.; RT "Generalized arterial calcification of infancy: different clinical courses RT in two affected siblings."; RL Am. J. Med. Genet. A 136:210-213(2005). RN [24] RP VARIANT GLN-173, AND INVOLVEMENT IN T2D. RX PubMed=16186408; DOI=10.2337/diabetes.54.10.3021; RA Bacci S., Ludovico O., Prudente S., Zhang Y.Y., Di Paola R., RA Mangiacotti D., Rauseo A., Nolan D., Duffy J., Fini G., Salvemini L., RA Amico C., Vigna C., Pellegrini F., Menzaghi C., Doria A., Trischitta V.; RT "The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin RT resistance/atherogenic phenotypes, including earlier onset of type 2 RT diabetes and myocardial infarction."; RL Diabetes 54:3021-3025(2005). RN [25] RP VARIANTS GACI1 LEU-250; TYR-252 DEL; THR-305; VAL-342 AND PHE-371, AND RP VARIANT CYS-774. RX PubMed=15605415; DOI=10.1002/humu.9297; RA Ruf N., Uhlenberg B., Terkeltaub R., Nurnberg P., Rutsch F.; RT "The mutational spectrum of ENPP1 as arising after the analysis of 23 RT unrelated patients with generalized arterial calcification of infancy RT (GACI)."; RL Hum. Mutat. 25:98-98(2005). RN [26] RP VARIANTS GACI1 ARG-126; TYR-216; GLU-242; LEU-250; ASN-276; THR-305; RP VAL-342; LYS-349; PHE-371; GLN-456; CYS-471; TRP-481; PRO-500; ARG-504; RP CYS-513; CYS-570; PHE-579; CYS-659; ARG-726; ARG-777; SER-792; HIS-804 AND RP TRP-888, AND VARIANTS VAL-611; LYS-668; CYS-774 AND HIS-821. RX PubMed=20016754; DOI=10.1161/circgenetics.108.797704; RG GACI Study Group; RA Rutsch F., Boeyer P., Nitschke Y., Ruf N., Lorenz-Depierieux B., RA Wittkampf T., Weissen-Plenz G., Fischer R.J., Mughal Z., Gregory J.W., RA Davies J.H., Loirat C., Strom T.M., Schnabel D., Nuernberg P., RA Terkeltaub R.; RT "Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are RT associated with survival beyond infancy in generalized arterial RT calcification of infancy."; RL Circ. Cardiovasc. Genet. 1:133-140(2008). RN [27] RP VARIANT ARHR2 VAL-266. RX PubMed=20137773; DOI=10.1016/j.ajhg.2010.01.006; RA Lorenz-Depiereux B., Schnabel D., Tiosano D., Hausler G., Strom T.M.; RT "Loss-of-function ENPP1 mutations cause both generalized arterial RT calcification of infancy and autosomal-recessive hypophosphatemic RT rickets."; RL Am. J. Hum. Genet. 86:267-272(2010). RN [28] RP VARIANT ARHR2 SER-901, AND CHARACTERIZATION OF VARIANT ARHR2 SER-901. RX PubMed=20137772; DOI=10.1016/j.ajhg.2010.01.010; RA Levy-Litan V., Hershkovitz E., Avizov L., Leventhal N., Bercovich D., RA Chalifa-Caspi V., Manor E., Buriakovsky S., Hadad Y., Goding J., RA Parvari R.; RT "Autosomal-recessive hypophosphatemic rickets is associated with an RT inactivation mutation in the ENPP1 gene."; RL Am. J. Hum. Genet. 86:273-278(2010). RN [29] RP VARIANT GLN-173. RX PubMed=20034067; DOI=10.1002/ajmg.a.33162; RA Le Boulanger G., Labreze C., Croue A., Schurgers L.J., Chassaing N., RA Wittkampf T., Rutsch F., Martin L.; RT "An unusual severe vascular case of pseudoxanthoma elasticum presenting as RT generalized arterial calcification of infancy."; RL Am. J. Med. Genet. A 152:118-123(2010). RN [30] RP VARIANT GACI1 VAL-218. RX PubMed=23430823; DOI=10.1007/8904_2011_11; RA Galletti S., Nitschke Y., Malavolti A.M., Aquilano G., Faldella G., RA Corvaglia L., Rutsch F.; RT "Generalized arterial calcification of infancy: fatal clinical course RT associated with a novel mutation in ENPP1."; RL JIMD Rep. 1:23-27(2011). RN [31] RP VARIANTS GACI1 HIS-538 AND ARG-586. RX PubMed=22209248; DOI=10.1016/j.ajhg.2011.11.020; RA Nitschke Y., Baujat G., Botschen U., Wittkampf T., du Moulin M., Stella J., RA Le Merrer M., Guest G., Lambot K., Tazarourte-Pinturier M.F., Chassaing N., RA Roche O., Feenstra I., Loechner K., Deshpande C., Garber S.J., RA Chikarmane R., Steinmann B., Shahinyan T., Martorell L., Davies J., RA Smith W.E., Kahler S.G., McCulloch M., Wraige E., Loidi L., Hohne W., RA Martin L., Hadj-Rabia S., Terkeltaub R., Rutsch F.; RT "Generalized arterial calcification of infancy and pseudoxanthoma elasticum RT can be caused by mutations in either ENPP1 or ABCC6."; RL Am. J. Hum. Genet. 90:25-39(2012). RN [32] RP VARIANTS COLED SER-149; SER-164 AND TYR-177. RX PubMed=24075184; DOI=10.1016/j.ajhg.2013.08.007; RA Eytan O., Morice-Picard F., Sarig O., Ezzedine K., Isakov O., Li Q., RA Ishida-Yamamoto A., Shomron N., Goldsmith T., Fuchs-Telem D., Adir N., RA Uitto J., Orlow S.J., Taieb A., Sprecher E.; RT "Cole disease results from mutations in ENPP1."; RL Am. J. Hum. Genet. 93:752-757(2013). RN [33] RP VARIANTS ARHR2 ASP-92; ARG-219 AND SER-792, AND INVOLVEMENT IN ARHR2. RX PubMed=25741938; DOI=10.1515/jpem-2014-0531; RA Steichen-Gersdorf E., Lorenz-Depiereux B., Strom T.M., Shaw N.J.; RT "Early onset hearing loss in autosomal recessive hypophosphatemic rickets RT caused by loss of function mutation in ENPP1."; RL J. Pediatr. Endocrinol. Metab. 28:967-970(2015). RN [34] RP VARIANTS COLED ARG-133 AND SER-177. RX PubMed=26617416; DOI=10.1111/bjd.14328; RA Schlipf N.A., Traupe H., Gilaberte Y., Peitsch W.K., Hausser I., Oji V., RA Schmieder A., Schneider S.W., Demmer P., Roesler B., Fischer J.; RT "Association of Cole disease with novel heterozygous mutations in the RT somatomedin-B domains of the ENPP1 gene: necessary, but not always RT sufficient."; RL Br. J. Dermatol. 174:1152-1156(2016). RN [35] RP VARIANTS GACI1 ARG-195; SER-195 AND CYS-301, CHARACTERIZATION OF VARIANTS RP GLN-173; LYS-668; CYS-774 AND HIS-821, CHARACTERIZATION OF VARIANTS GACI1 RP ARG-195; SER-195; CYS-301; THR-305; CYS-471; ARG-504; CYS-513; HIS-538; RP ARG-586; CYS-659; ARG-777 AND TRP-888, FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=27467858; DOI=10.1002/humu.23057; RA Stella J., Buers I., van de Wetering K., Hoehne W., Rutsch F., Nitschke Y.; RT "Effects of Different Variants in the ENPP1 Gene on the Functional RT Properties of Ectonucleotide Pyrophosphatase/Phosphodiesterase Family RT Member 1."; RL Hum. Mutat. 37:1190-1201(2016). RN [36] RP VARIANT COLED ARG-120, CHARACTERIZATION OF VARIANTS COLED ARG-120 AND RP SER-164, TISSUE SPECIFICITY, FUNCTION, AND SUBUNIT. RX PubMed=28964717; DOI=10.1016/j.jid.2017.08.045; RA Chourabi M., Liew M.S., Lim S., H'mida-Ben Brahim D., Boussofara L., RA Dai L., Wong P.M., Foo J.N., Sriha B., Robinson K.S., Denil S., RA Common J.E., Mamai O., Ben Khalifa Y., Bollen M., Liu J., Denguezli M., RA Bonnard C., Saad A., Reversade B.; RT "ENPP1 mutation causes recessive cole disease by altering melanogenesis."; RL J. Invest. Dermatol. 138:291-300(2018). RN [37] RP VARIANT GLN-173, AND INVOLVEMENT IN T2D. RX PubMed=29958952; DOI=10.1016/j.gene.2018.06.006; RA Sharafshah A., Keshavarz P., Rezaei S., Farhadian N.; RT "Association and in silico studies of ENPP1 gene variants with type 2 RT diabetes mellitus in a Northern Iranian population."; RL Gene 675:225-232(2018). CC -!- FUNCTION: Nucleotide pyrophosphatase that generates diphosphate (PPi) CC and functions in bone mineralization and soft tissue calcification by CC regulating pyrophosphate levels (By similarity). PPi inhibits bone CC mineralization and soft tissue calcification by binding to nascent CC hydroxyapatite crystals, thereby preventing further growth of these CC crystals (PubMed:11004006). Preferentially hydrolyzes ATP, but can also CC hydrolyze other nucleoside 5' triphosphates such as GTP, CTP and UTP to CC their corresponding monophosphates with release of pyrophosphate, as CC well as diadenosine polyphosphates, and also 3',5'-cAMP to AMP CC (PubMed:27467858, PubMed:8001561, PubMed:25344812, PubMed:28011303, CC PubMed:35147247). May also be involved in the regulation of the CC availability of nucleotide sugars in the endoplasmic reticulum and CC Golgi, and the regulation of purinergic signaling (PubMed:27467858, CC PubMed:8001561). Inhibits ectopic joint calcification and maintains CC articular chondrocytes by repressing hedgehog signaling; it is however CC unclear whether hedgehog inhibition is direct or indirect (By CC similarity). Appears to modulate insulin sensitivity and function CC (PubMed:10615944). Also involved in melanogenesis (PubMed:28964717). CC Also able to hydrolyze 2',3'-cGAMP (cyclic GMP-AMP), a second messenger CC that activates TMEM173/STING and triggers type-I interferon production CC (PubMed:25344812). 2',3'-cGAMP degradation takes place in the lumen or CC extracellular space, and not in the cytosol where it is produced; the CC role of 2',3'-cGAMP hydrolysis is therefore unclear (PubMed:25344812). CC Not able to hydrolyze the 2',3'-cGAMP linkage isomer 3'-3'-cGAMP CC (PubMed:25344812). {ECO:0000250|UniProtKB:P06802, CC ECO:0000269|PubMed:10615944, ECO:0000269|PubMed:25344812, CC ECO:0000269|PubMed:27467858, ECO:0000269|PubMed:28011303, CC ECO:0000269|PubMed:28964717, ECO:0000269|PubMed:35147247, CC ECO:0000269|PubMed:8001561, ECO:0000305|PubMed:11004006}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Hydrolytically removes 5'-nucleotides successively from the CC 3'-hydroxy termini of 3'-hydroxy-terminated oligonucleotides.; CC EC=3.1.4.1; Evidence={ECO:0000269|PubMed:8001561}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'- CC phosphate + diphosphate + H(+); Xref=Rhea:RHEA:23996, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:33019, CC ChEBI:CHEBI:58043, ChEBI:CHEBI:61557; EC=3.6.1.9; CC Evidence={ECO:0000269|PubMed:25344812, ECO:0000269|PubMed:28011303}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23997; CC Evidence={ECO:0000269|PubMed:25344812, ECO:0000269|PubMed:35147247}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + H2O = AMP + diphosphate + H(+); Xref=Rhea:RHEA:14245, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:33019, ChEBI:CHEBI:456215; EC=3.6.1.9; CC Evidence={ECO:0000269|PubMed:25344812, ECO:0000269|PubMed:28011303}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + UTP = diphosphate + H(+) + UMP; Xref=Rhea:RHEA:29395, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:33019, CC ChEBI:CHEBI:46398, ChEBI:CHEBI:57865; EC=3.6.1.9; CC Evidence={ECO:0000269|PubMed:28011303}; CC -!- CATALYTIC ACTIVITY: CC Reaction=GTP + H2O = diphosphate + GMP + H(+); Xref=Rhea:RHEA:29391, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:33019, CC ChEBI:CHEBI:37565, ChEBI:CHEBI:58115; EC=3.6.1.9; CC Evidence={ECO:0000250|UniProtKB:P06802}; CC -!- CATALYTIC ACTIVITY: CC Reaction=CTP + H2O = CMP + diphosphate + H(+); Xref=Rhea:RHEA:27762, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:33019, CC ChEBI:CHEBI:37563, ChEBI:CHEBI:60377; EC=3.6.1.9; CC Evidence={ECO:0000250|UniProtKB:P06802}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2',3'-cGAMP + 2 H2O = AMP + GMP + 2 H(+); CC Xref=Rhea:RHEA:58808, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:58115, ChEBI:CHEBI:143093, ChEBI:CHEBI:456215; CC Evidence={ECO:0000269|PubMed:25344812, ECO:0000269|PubMed:28011303}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58809; CC Evidence={ECO:0000269|PubMed:25344812}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + P(1),P(4)-bis(5'-adenosyl) tetraphosphate = AMP + ATP + CC 2 H(+); Xref=Rhea:RHEA:32039, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:58141, ChEBI:CHEBI:456215; CC Evidence={ECO:0000269|PubMed:28011303}; CC -!- CATALYTIC ACTIVITY: CC Reaction=3',5'-cyclic AMP + H2O = AMP + H(+); Xref=Rhea:RHEA:25277, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:58165, CC ChEBI:CHEBI:456215; Evidence={ECO:0000269|PubMed:28011303}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000250|UniProtKB:P06802}; CC Note=Binds 2 Zn(2+) ions per subunit. {ECO:0000250|UniProtKB:P06802}; CC -!- ACTIVITY REGULATION: At low concentrations of ATP, a phosphorylated CC intermediate is formed which inhibits further hydrolysis. CC {ECO:0000250|UniProtKB:P06802}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=8.17 uM for ATP {ECO:0000269|PubMed:28011303}; CC KM=20.5 uM for AP4A (P(1),P(4)-bis(5'-adenosyl) tetraphosphate) CC {ECO:0000269|PubMed:28011303}; CC KM=32.6 uM for 2',3'-cGAMP {ECO:0000269|PubMed:28011303}; CC KM=56.6 uM for UTP {ECO:0000269|PubMed:28011303}; CC KM=114 uM for 3',5'-cyclic AMP {ECO:0000269|PubMed:28011303}; CC KM=15 uM for 2',3'-cGAMP {ECO:0000269|PubMed:25344812}; CC KM=20 uM for ATP {ECO:0000269|PubMed:25344812}; CC Note=kcat is 5.51 sec(-1) with ATP as substrate (PubMed:28011303). CC kcat is 5.65 sec(-1) with AP4A as substrate (PubMed:28011303). kcat CC is 5.36 sec(-1) with 2',3'-cGAMP as substrate (PubMed:28011303). kcat CC is 1.96 sec(-1) with UTP as substrate (PubMed:28011303). kcat is 2.16 CC sec(-1) with 3',5'-cyclic AMP as substrate (PubMed:28011303). kcat is CC kcat is 4 sec(-1) with 2',3'-cGAMP as substrate (PubMed:25344812). CC kcat is 12 sec(-1) with ATP as substrate (PubMed:25344812). CC {ECO:0000269|PubMed:25344812, ECO:0000269|PubMed:28011303}; CC -!- SUBUNIT: [Ectonucleotide pyrophosphatase/phosphodiesterase family CC member 1]: Homodimer (PubMed:28964717). Interacts with INSR; leading to CC inhibit INSR autophosphorylation and subsequent activation of INSR CC kinase activity (PubMed:10615944). {ECO:0000269|PubMed:10615944, CC ECO:0000269|PubMed:28964717}. CC -!- SUBUNIT: [Ectonucleotide pyrophosphatase/phosphodiesterase family CC member 1, secreted form]: Monomeric (By similarity). CC {ECO:0000250|UniProtKB:P06802}. CC -!- INTERACTION: CC P22413; Q9UNQ0: ABCG2; NbExp=4; IntAct=EBI-3197846, EBI-1569435; CC -!- SUBCELLULAR LOCATION: [Ectonucleotide pyrophosphatase/phosphodiesterase CC family member 1]: Cell membrane {ECO:0000269|PubMed:15072822, CC ECO:0000269|PubMed:27467858, ECO:0000269|PubMed:8001561}; Single-pass CC type II membrane protein. Basolateral cell membrane CC {ECO:0000269|PubMed:11598187}; Single-pass type II membrane protein. CC Note=Targeted to the basolateral membrane in polarized epithelial cells CC and in hepatocytes, and to matrix vesicles in osteoblasts CC (PubMed:11598187). In bile duct cells and cancer cells, located to the CC apical cytoplasmic side (PubMed:11598187). CC {ECO:0000269|PubMed:11598187}. CC -!- SUBCELLULAR LOCATION: [Ectonucleotide pyrophosphatase/phosphodiesterase CC family member 1, secreted form]: Secreted CC {ECO:0000250|UniProtKB:P06802}. Note=Secreted following proteolytic CC cleavage. {ECO:0000250|UniProtKB:P06802}. CC -!- TISSUE SPECIFICITY: Expressed in plasma cells and also in a number of CC non-lymphoid tissues, including the distal convoluted tubule of the CC kidney, chondrocytes and epididymis (PubMed:9344668). Expressed in CC melanocytes but not in keratinocytes (PubMed:28964717). CC {ECO:0000269|PubMed:28964717, ECO:0000269|PubMed:9344668}. CC -!- DOMAIN: The di-leucine motif is required for basolateral targeting in CC epithelial cells, and for targeting to matrix vesicles derived from CC mineralizing cells. {ECO:0000250|UniProtKB:P06802}. CC -!- PTM: Autophosphorylated as part of the catalytic cycle of CC phosphodiesterase/pyrophosphatase activity. CC {ECO:0000305|PubMed:7737162}. CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:19159218, CC ECO:0000269|PubMed:19349973, ECO:0000269|PubMed:8001561}. CC -!- PTM: The secreted form is produced through cleavage at Lys-103 by CC intracellular processing. {ECO:0000250|UniProtKB:P06802}. CC -!- DISEASE: Ossification of the posterior longitudinal ligament of the CC spine (OPLL) [MIM:602475]: A calcification of the posterior CC longitudinal ligament of the spinal column, usually at the level of the CC cervical spine. Patients with OPLL frequently present with a severe CC myelopathy that can lead to tetraparesis. CC {ECO:0000269|PubMed:10453738}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Arterial calcification of infancy, generalized, 1 (GACI1) CC [MIM:208000]: A severe autosomal recessive disorder characterized by CC calcification of the internal elastic lamina of muscular arteries and CC stenosis due to myointimal proliferation. The disorder is often fatal CC within the first 6 months of life because of myocardial ischemia CC resulting in refractory heart failure. {ECO:0000269|PubMed:12881724, CC ECO:0000269|PubMed:15605415, ECO:0000269|PubMed:15940697, CC ECO:0000269|PubMed:20016754, ECO:0000269|PubMed:22209248, CC ECO:0000269|PubMed:23430823, ECO:0000269|PubMed:27467858}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Type 2 diabetes mellitus (T2D) [MIM:125853]: A multifactorial CC disorder of glucose homeostasis caused by a lack of sensitivity to the CC body's own insulin. Affected individuals usually have an obese body CC habitus and manifestations of a metabolic syndrome characterized by CC diabetes, insulin resistance, hypertension and hypertriglyceridemia. CC The disease results in long-term complications that affect the eyes, CC kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:16186408, CC ECO:0000269|PubMed:29958952}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Hypophosphatemic rickets, autosomal recessive, 2 (ARHR2) CC [MIM:613312]: A hereditary form of hypophosphatemic rickets, a disorder CC of proximal renal tubule function that causes phosphate loss, CC hypophosphatemia and skeletal deformities, including rickets and CC osteomalacia unresponsive to vitamin D. Symptoms are bone pain, CC fractures and growth abnormalities. {ECO:0000269|PubMed:20137772, CC ECO:0000269|PubMed:20137773, ECO:0000269|PubMed:25741938}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Cole disease (COLED) [MIM:615522]: A rare autosomal dominant CC genodermatosis characterized by punctate keratoderma associated with CC irregularly shaped hypopigmented macules, which are typically found CC over the arms and legs but not the trunk or acral regions. Skin CC biopsies of palmoplantar lesions show hyperorthokeratosis, CC hypergranulosis, and acanthosis. Hypopigmented areas of skin, however, CC reveal a reduction in melanin content in keratinocytes but not in CC melanocytes, as well as hyperkeratosis and a normal number of CC melanocytes. Ultrastructurally, melanocytes show a disproportionately CC large number of melanosomes in the cytoplasm and dendrites, whereas CC keratinocytes show a paucity of these organelles, suggestive of CC impaired melanosome transfer. Some patients also exhibit calcinosis CC cutis or calcific tendinopathy. {ECO:0000269|PubMed:24075184, CC ECO:0000269|PubMed:26617416, ECO:0000269|PubMed:28964717}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the nucleotide pyrophosphatase/phosphodiesterase CC family. {ECO:0000305}. CC -!- CAUTION: It is uncertain whether Met-1 or Met-53 is the initiator. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA63237.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH59375.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAA02054.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M57736; AAA63237.1; ALT_INIT; mRNA. DR EMBL; D12485; BAA02054.1; ALT_INIT; mRNA. DR EMBL; AF110304; AAF36094.1; -; Genomic_DNA. DR EMBL; AF110280; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110281; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110283; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110284; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110285; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110286; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110287; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110288; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110289; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110290; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110291; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110292; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110293; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110294; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110295; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110296; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110297; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110298; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110299; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110300; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110301; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110302; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AF110303; AAF36094.1; JOINED; Genomic_DNA. DR EMBL; AJ242020; CAC39442.1; -; Genomic_DNA. DR EMBL; AJ242021; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242022; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242023; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242024; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242025; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242026; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242027; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242028; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242029; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242030; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242031; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242032; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242033; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242034; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242035; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242036; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242037; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242038; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242039; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242040; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242041; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242042; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242043; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AJ242044; CAC39442.1; JOINED; Genomic_DNA. DR EMBL; AL117378; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL139805; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC059375; AAH59375.2; ALT_INIT; mRNA. DR EMBL; AF067177; AAD38420.1; -; Genomic_DNA. DR EMBL; AF067178; AAD38421.1; -; Genomic_DNA. DR CCDS; CCDS5150.2; -. DR PIR; A39216; A39216. DR RefSeq; NP_006199.2; NM_006208.2. DR PDB; 2YS0; NMR; -; A=147-189. DR PDB; 6WET; X-ray; 2.60 A; AaA/BaB=1-925. DR PDB; 6WEU; X-ray; 2.65 A; AbA/BbB=1-925. DR PDB; 6WEV; X-ray; 2.90 A; AbA/BbB=1-925. DR PDB; 6WEW; X-ray; 2.73 A; AbA/BaB=1-925. DR PDB; 6WFJ; X-ray; 2.50 A; AcA/BcB=1-925. DR PDB; 8GHR; EM; 3.20 A; A/B=186-925. DR PDBsum; 2YS0; -. DR PDBsum; 6WET; -. DR PDBsum; 6WEU; -. DR PDBsum; 6WEV; -. DR PDBsum; 6WEW; -. DR PDBsum; 6WFJ; -. DR PDBsum; 8GHR; -. DR AlphaFoldDB; P22413; -. DR BMRB; P22413; -. DR SMR; P22413; -. DR BioGRID; 111193; 51. DR IntAct; P22413; 14. DR MINT; P22413; -. DR STRING; 9606.ENSP00000498074; -. DR BindingDB; P22413; -. DR ChEMBL; CHEMBL5925; -. DR DrugBank; DB11077; Polyethylene glycol 400. DR DrugBank; DB06408; Taribavirin. DR DrugCentral; P22413; -. DR GlyConnect; 1196; 19 N-Linked glycans (2 sites). DR GlyCosmos; P22413; 9 sites, 18 glycans. DR GlyGen; P22413; 10 sites, 18 N-linked glycans (2 sites), 1 O-linked glycan (1 site). DR iPTMnet; P22413; -. DR PhosphoSitePlus; P22413; -. DR SwissPalm; P22413; -. DR BioMuta; ENPP1; -. DR DMDM; 23503088; -. DR EPD; P22413; -. DR jPOST; P22413; -. DR MassIVE; P22413; -. DR MaxQB; P22413; -. DR PaxDb; 9606-ENSP00000354238; -. DR PeptideAtlas; P22413; -. DR ProteomicsDB; 53988; -. DR Pumba; P22413; -. DR Antibodypedia; 32916; 453 antibodies from 36 providers. DR DNASU; 5167; -. DR Ensembl; ENST00000647893.1; ENSP00000498074.1; ENSG00000197594.14. DR GeneID; 5167; -. DR KEGG; hsa:5167; -. DR MANE-Select; ENST00000647893.1; ENSP00000498074.1; NM_006208.3; NP_006199.2. DR UCSC; uc011ecf.2; human. DR AGR; HGNC:3356; -. DR CTD; 5167; -. DR DisGeNET; 5167; -. DR GeneCards; ENPP1; -. DR GeneReviews; ENPP1; -. DR HGNC; HGNC:3356; ENPP1. DR HPA; ENSG00000197594; Tissue enhanced (placenta). DR MalaCards; ENPP1; -. DR MIM; 125853; phenotype. DR MIM; 173335; gene. DR MIM; 208000; phenotype. DR MIM; 602475; phenotype. DR MIM; 613312; phenotype. DR MIM; 615522; phenotype. DR neXtProt; NX_P22413; -. DR OpenTargets; ENSG00000197594; -. DR Orphanet; 289176; Autosomal recessive hypophosphatemic rickets. DR Orphanet; 51608; Generalized arterial calcification of infancy. DR Orphanet; 324561; Hypopigmentation-punctate palmoplantar keratoderma syndrome. DR Orphanet; 758; Pseudoxanthoma elasticum. DR PharmGKB; PA27791; -. DR VEuPathDB; HostDB:ENSG00000197594; -. DR eggNOG; KOG2645; Eukaryota. DR GeneTree; ENSGT00940000156034; -. DR HOGENOM; CLU_012256_0_1_1; -. DR InParanoid; P22413; -. DR OMA; FQVIWQY; -. DR OrthoDB; 1366859at2759; -. DR PhylomeDB; P22413; -. DR TreeFam; TF330032; -. DR BRENDA; 3.6.1.9; 2681. DR PathwayCommons; P22413; -. DR Reactome; R-HSA-196843; Vitamin B2 (riboflavin) metabolism. DR Reactome; R-HSA-199220; Vitamin B5 (pantothenate) metabolism. DR SABIO-RK; P22413; -. DR SignaLink; P22413; -. DR SIGNOR; P22413; -. DR BioGRID-ORCS; 5167; 14 hits in 1158 CRISPR screens. DR ChiTaRS; ENPP1; human. DR EvolutionaryTrace; P22413; -. DR GeneWiki; Ectonucleotide_pyrophosphatase/phosphodiesterase_1; -. DR GenomeRNAi; 5167; -. DR Pharos; P22413; Tchem. DR PRO; PR:P22413; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; P22413; Protein. DR Bgee; ENSG00000197594; Expressed in tibia and 165 other cell types or tissues. DR ExpressionAtlas; P22413; baseline and differential. DR GO; GO:0016323; C:basolateral plasma membrane; NAS:BHF-UCL. DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL. DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL. DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB. DR GO; GO:0016020; C:membrane; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IEA:RHEA. DR GO; GO:0050656; F:3'-phosphoadenosine 5'-phosphosulfate binding; IC:BHF-UCL. DR GO; GO:0005524; F:ATP binding; IDA:BHF-UCL. DR GO; GO:0047693; F:ATP diphosphatase activity; IEA:RHEA. DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB. DR GO; GO:0106177; F:cyclic-GMP-AMP hydrolase activity; IDA:UniProtKB. DR GO; GO:0004551; F:dinucleotide phosphatase activity; IDA:BHF-UCL. DR GO; GO:0004527; F:exonuclease activity; IDA:UniProtKB. DR GO; GO:0036219; F:GTP diphosphatase activity; IEA:RHEA. DR GO; GO:0005158; F:insulin receptor binding; IDA:BHF-UCL. DR GO; GO:0003676; F:nucleic acid binding; IEA:InterPro. DR GO; GO:0047429; F:nucleoside triphosphate diphosphatase activity; IDA:UniProtKB. DR GO; GO:0016791; F:phosphatase activity; IDA:MGI. DR GO; GO:0004528; F:phosphodiesterase I activity; IDA:UniProtKB. DR GO; GO:0030247; F:polysaccharide binding; IEA:InterPro. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0005044; F:scavenger receptor activity; IEA:InterPro. DR GO; GO:0036221; F:UTP diphosphatase activity; IEA:RHEA. DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB. DR GO; GO:0050427; P:3'-phosphoadenosine 5'-phosphosulfate metabolic process; IDA:BHF-UCL. DR GO; GO:0046034; P:ATP metabolic process; IDA:MGI. DR GO; GO:0030282; P:bone mineralization; IDA:MGI. DR GO; GO:0032869; P:cellular response to insulin stimulus; IDA:BHF-UCL. DR GO; GO:0010467; P:gene expression; IDA:MGI. DR GO; GO:0006091; P:generation of precursor metabolites and energy; IDA:BHF-UCL. DR GO; GO:0006955; P:immune response; IEA:InterPro. DR GO; GO:0030505; P:inorganic diphosphate transport; IDA:BHF-UCL. DR GO; GO:0030643; P:intracellular phosphate ion homeostasis; IDA:BHF-UCL. DR GO; GO:0030318; P:melanocyte differentiation; IMP:UniProtKB. DR GO; GO:0030502; P:negative regulation of bone mineralization; ISS:UniProtKB. DR GO; GO:0030308; P:negative regulation of cell growth; IDA:BHF-UCL. DR GO; GO:0045599; P:negative regulation of fat cell differentiation; IDA:BHF-UCL. DR GO; GO:0046325; P:negative regulation of glucose import; IDA:BHF-UCL. DR GO; GO:0045719; P:negative regulation of glycogen biosynthetic process; IDA:BHF-UCL. DR GO; GO:1990787; P:negative regulation of hh target transcription factor activity; ISS:UniProtKB. DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0031953; P:negative regulation of protein autophosphorylation; IDA:BHF-UCL. DR GO; GO:0090304; P:nucleic acid metabolic process; IDA:UniProtKB. DR GO; GO:0009143; P:nucleoside triphosphate catabolic process; IDA:BHF-UCL. DR GO; GO:0055062; P:phosphate ion homeostasis; IDA:MGI. DR GO; GO:0006796; P:phosphate-containing compound metabolic process; IDA:BHF-UCL. DR GO; GO:0030500; P:regulation of bone mineralization; IBA:GO_Central. DR GO; GO:0033198; P:response to ATP; IDA:MGI. DR GO; GO:0010035; P:response to inorganic substance; IDA:MGI. DR GO; GO:0030730; P:sequestering of triglyceride; IDA:BHF-UCL. DR CDD; cd16018; Enpp; 1. DR CDD; cd00091; NUC; 1. DR Gene3D; 4.10.410.20; -; 2. DR Gene3D; 3.40.720.10; Alkaline Phosphatase, subunit A; 1. DR Gene3D; 3.40.570.10; Extracellular Endonuclease, subunit A; 1. DR InterPro; IPR017850; Alkaline_phosphatase_core_sf. DR InterPro; IPR001604; DNA/RNA_non-sp_Endonuclease. DR InterPro; IPR044929; DNA/RNA_non-sp_Endonuclease_sf. DR InterPro; IPR020821; Extracellular_endonuc_su_A. DR InterPro; IPR044925; His-Me_finger_sf. DR InterPro; IPR002591; Phosphodiest/P_Trfase. DR InterPro; IPR020436; SMB_chordata. DR InterPro; IPR036024; Somatomedin_B-like_dom_sf. DR InterPro; IPR001212; Somatomedin_B_dom. DR PANTHER; PTHR10151; ECTONUCLEOTIDE PYROPHOSPHATASE/PHOSPHODIESTERASE; 1. DR PANTHER; PTHR10151:SF77; ECTONUCLEOTIDE PYROPHOSPHATASE_PHOSPHODIESTERASE FAMILY MEMBER 1; 1. DR Pfam; PF01223; Endonuclease_NS; 1. DR Pfam; PF01663; Phosphodiest; 1. DR Pfam; PF01033; Somatomedin_B; 2. DR PRINTS; PR00022; SOMATOMEDINB. DR SMART; SM00892; Endonuclease_NS; 1. DR SMART; SM00477; NUC; 1. DR SMART; SM00201; SO; 2. DR SUPFAM; SSF53649; Alkaline phosphatase-like; 1. DR SUPFAM; SSF54060; His-Me finger endonucleases; 1. DR SUPFAM; SSF90188; Somatomedin B domain; 2. DR PROSITE; PS00524; SMB_1; 2. DR PROSITE; PS50958; SMB_2; 2. DR Genevisible; P22413; HS. PE 1: Evidence at protein level; KW 3D-structure; Biomineralization; Calcium; Cell membrane; Diabetes mellitus; KW Direct protein sequencing; Disease variant; Disulfide bond; Glycoprotein; KW Hydrolase; Membrane; Metal-binding; Obesity; Phosphoprotein; KW Reference proteome; Repeat; Secreted; Signal-anchor; Transmembrane; KW Transmembrane helix; Zinc. FT CHAIN 1..925 FT /note="Ectonucleotide pyrophosphatase/phosphodiesterase FT family member 1" FT /id="PRO_0000188564" FT CHAIN 103..925 FT /note="Ectonucleotide pyrophosphatase/phosphodiesterase FT family member 1, secreted form" FT /evidence="ECO:0000250|UniProtKB:P06802" FT /id="PRO_0000447133" FT TOPO_DOM 1..76 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 77..97 FT /note="Helical; Signal-anchor for type II membrane protein" FT /evidence="ECO:0000255" FT TOPO_DOM 98..925 FT /note="Extracellular" FT /evidence="ECO:0000255" FT DOMAIN 104..144 FT /note="SMB 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DOMAIN 145..189 FT /note="SMB 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT REGION 1..43 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 191..591 FT /note="Phosphodiesterase" FT /evidence="ECO:0000250|UniProtKB:P06802" FT REGION 597..647 FT /note="Linker" FT /evidence="ECO:0000250|UniProtKB:P06802" FT REGION 654..925 FT /note="Nuclease" FT /evidence="ECO:0000250|UniProtKB:P06802" FT MOTIF 45..52 FT /note="Di-leucine motif" FT /evidence="ECO:0000250|UniProtKB:P06802" FT ACT_SITE 256 FT /note="AMP-threonine intermediate" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 218 FT /ligand="AMP" FT /ligand_id="ChEBI:CHEBI:456215" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 218 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 256 FT /ligand="AMP" FT /ligand_id="ChEBI:CHEBI:456215" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 256 FT /ligand="CMP" FT /ligand_id="ChEBI:CHEBI:60377" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 256 FT /ligand="dTMP" FT /ligand_id="ChEBI:CHEBI:63528" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 256 FT /ligand="GMP" FT /ligand_id="ChEBI:CHEBI:58115" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 256 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 277 FT /ligand="AMP" FT /ligand_id="ChEBI:CHEBI:456215" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 277 FT /ligand="CMP" FT /ligand_id="ChEBI:CHEBI:60377" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 277 FT /ligand="dTMP" FT /ligand_id="ChEBI:CHEBI:63528" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 277 FT /ligand="GMP" FT /ligand_id="ChEBI:CHEBI:58115" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 290 FT /ligand="GMP" FT /ligand_id="ChEBI:CHEBI:58115" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 295 FT /ligand="AMP" FT /ligand_id="ChEBI:CHEBI:456215" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 295 FT /ligand="CMP" FT /ligand_id="ChEBI:CHEBI:60377" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 295 FT /ligand="GMP" FT /ligand_id="ChEBI:CHEBI:58115" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 340 FT /ligand="AMP" FT /ligand_id="ChEBI:CHEBI:456215" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 340 FT /ligand="CMP" FT /ligand_id="ChEBI:CHEBI:60377" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 340 FT /ligand="dTMP" FT /ligand_id="ChEBI:CHEBI:63528" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 340 FT /ligand="GMP" FT /ligand_id="ChEBI:CHEBI:58115" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 376 FT /ligand="AMP" FT /ligand_id="ChEBI:CHEBI:456215" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 376 FT /ligand="CMP" FT /ligand_id="ChEBI:CHEBI:60377" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 376 FT /ligand="dTMP" FT /ligand_id="ChEBI:CHEBI:63528" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 376 FT /ligand="GMP" FT /ligand_id="ChEBI:CHEBI:58115" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 376 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 380 FT /ligand="2',3'-cGAMP" FT /ligand_id="ChEBI:CHEBI:143093" FT /ligand_note="substrate" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 380 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 423 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 424 FT /ligand="AMP" FT /ligand_id="ChEBI:CHEBI:456215" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 424 FT /ligand="CMP" FT /ligand_id="ChEBI:CHEBI:60377" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 424 FT /ligand="dTMP" FT /ligand_id="ChEBI:CHEBI:63528" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 424 FT /ligand="GMP" FT /ligand_id="ChEBI:CHEBI:58115" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 424 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 532 FT /ligand="2',3'-cGAMP" FT /ligand_id="ChEBI:CHEBI:143093" FT /ligand_note="substrate" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 535 FT /ligand="AMP" FT /ligand_id="ChEBI:CHEBI:456215" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 535 FT /ligand="CMP" FT /ligand_id="ChEBI:CHEBI:60377" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 535 FT /ligand="dTMP" FT /ligand_id="ChEBI:CHEBI:63528" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 535 FT /ligand="GMP" FT /ligand_id="ChEBI:CHEBI:58115" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 535 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 800 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 802 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 804 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 806 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000250|UniProtKB:P06802" FT BINDING 808 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000250|UniProtKB:P06802" FT SITE 102..103 FT /note="Cleavage" FT /evidence="ECO:0000250|UniProtKB:P06802" FT SITE 915 FT /note="Essential for catalytic activity" FT /evidence="ECO:0000250|UniProtKB:Q9R1E6" FT MOD_RES 256 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q924C3" FT CARBOHYD 179 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 285 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 341 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:19349973" FT CARBOHYD 477 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 585 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 643 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973" FT CARBOHYD 700 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 731 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 748 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19349973" FT DISULFID 108..122 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 112..140 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 120..133 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 126..132 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 149..166 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 154..184 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 164..177 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 170..176 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 195..241 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 203..415 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 431..530 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 480..868 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 614..672 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 626..726 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 628..711 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT DISULFID 838..848 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00350" FT VARIANT 91 FT /note="L -> P (in OPLL)" FT /evidence="ECO:0000269|PubMed:10453738" FT /id="VAR_014141" FT VARIANT 92 FT /note="G -> D (in ARHR2)" FT /evidence="ECO:0000269|PubMed:25741938" FT /id="VAR_077255" FT VARIANT 120 FT /note="C -> R (in COLED; impaired homodimerization)" FT /evidence="ECO:0000269|PubMed:28964717" FT /id="VAR_081644" FT VARIANT 126 FT /note="C -> R (in GACI1)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077256" FT VARIANT 133 FT /note="C -> R (in COLED; impaired homodimerization)" FT /evidence="ECO:0000269|PubMed:26617416, FT ECO:0000269|PubMed:28964717" FT /id="VAR_077257" FT VARIANT 149 FT /note="C -> S (in COLED; dbSNP:rs397518477)" FT /evidence="ECO:0000269|PubMed:24075184" FT /id="VAR_070782" FT VARIANT 164 FT /note="C -> S (in COLED; dbSNP:rs397518476)" FT /evidence="ECO:0000269|PubMed:24075184" FT /id="VAR_070783" FT VARIANT 173 FT /note="K -> Q (associated with T2D; decreased nucleotide FT phosphodiesterase activity; no effect on localization to FT plasma membrane; dbSNP:rs1044498)" FT /evidence="ECO:0000269|PubMed:10453738, FT ECO:0000269|PubMed:10480624, ECO:0000269|PubMed:16186408, FT ECO:0000269|PubMed:20034067, ECO:0000269|PubMed:27467858, FT ECO:0000269|PubMed:29958952" FT /id="VAR_008873" FT VARIANT 177 FT /note="C -> S (in COLED)" FT /evidence="ECO:0000269|PubMed:26617416" FT /id="VAR_077258" FT VARIANT 177 FT /note="C -> Y (in COLED; dbSNP:rs397518475)" FT /evidence="ECO:0000269|PubMed:24075184" FT /id="VAR_070784" FT VARIANT 179 FT /note="N -> S (in dbSNP:rs2273411)" FT /id="VAR_037432" FT VARIANT 195 FT /note="C -> R (in GACI1; loss of nucleotide FT phosphodiesterase activity; loss of localization to plasma FT membrane; dbSNP:rs763457176)" FT /evidence="ECO:0000269|PubMed:27467858" FT /id="VAR_077259" FT VARIANT 195 FT /note="C -> S (in GACI1; loss of nucleotide FT phosphodiesterase activity; loss of localization to plasma FT membrane)" FT /evidence="ECO:0000269|PubMed:27467858" FT /id="VAR_077260" FT VARIANT 216 FT /note="S -> Y (in GACI1; uncertain significance; FT dbSNP:rs760786509)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077261" FT VARIANT 218 FT /note="D -> V (in GACI1; dbSNP:rs1231182870)" FT /evidence="ECO:0000269|PubMed:23430823" FT /id="VAR_077262" FT VARIANT 219 FT /note="G -> R (in ARHR2; uncertain significance)" FT /evidence="ECO:0000269|PubMed:25741938" FT /id="VAR_077263" FT VARIANT 242 FT /note="G -> E (in GACI1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077264" FT VARIANT 250 FT /note="P -> L (in GACI1; uncertain significance; FT dbSNP:rs754659608)" FT /evidence="ECO:0000269|PubMed:15605415, FT ECO:0000269|PubMed:20016754" FT /id="VAR_067910" FT VARIANT 252 FT /note="Missing (in GACI1)" FT /evidence="ECO:0000269|PubMed:15605415" FT /id="VAR_067911" FT VARIANT 266 FT /note="G -> V (in ARHR2; dbSNP:rs121908248)" FT /evidence="ECO:0000269|PubMed:20137773" FT /id="VAR_063719" FT VARIANT 268 FT /note="Y -> H (in dbSNP:rs17847050)" FT /evidence="ECO:0000269|PubMed:10453738" FT /id="VAR_014142" FT VARIANT 276 FT /note="D -> N (in GACI1; uncertain significance; FT dbSNP:rs143771474)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077265" FT VARIANT 287 FT /note="S -> F (in OPLL; dbSNP:rs190947144)" FT /evidence="ECO:0000269|PubMed:10453738" FT /id="VAR_014143" FT VARIANT 301 FT /note="Y -> C (in GACI1; loss of nucleotide FT phosphodiesterase activity; loss of localization to plasma FT membrane)" FT /evidence="ECO:0000269|PubMed:27467858" FT /id="VAR_077266" FT VARIANT 305 FT /note="P -> T (in GACI1; loss of nucleotide FT phosphodiesterase activity; no effect on localization to FT plasma membrane; dbSNP:rs374270497)" FT /evidence="ECO:0000269|PubMed:15605415, FT ECO:0000269|PubMed:20016754, ECO:0000269|PubMed:27467858" FT /id="VAR_067912" FT VARIANT 342 FT /note="G -> V (in GACI1; dbSNP:rs121918025)" FT /evidence="ECO:0000269|PubMed:15605415, FT ECO:0000269|PubMed:15940697, ECO:0000269|PubMed:20016754" FT /id="VAR_037433" FT VARIANT 349 FT /note="R -> K (in GACI1; uncertain significance; FT dbSNP:rs764735802)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077267" FT VARIANT 371 FT /note="Y -> F (in GACI1; uncertain significance; FT dbSNP:rs121918026)" FT /evidence="ECO:0000269|PubMed:15605415, FT ECO:0000269|PubMed:15940697, ECO:0000269|PubMed:20016754" FT /id="VAR_037434" FT VARIANT 456 FT /note="R -> Q (in GACI1; dbSNP:rs765071179)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077268" FT VARIANT 471 FT /note="Y -> C (in GACI1; decreased nucleotide FT phosphodiesterase activity; no effect on localization to FT plasma membrane; dbSNP:rs148462924)" FT /evidence="ECO:0000269|PubMed:20016754, FT ECO:0000269|PubMed:27467858" FT /id="VAR_077269" FT VARIANT 481 FT /note="R -> W (in GACI1; uncertain significance; FT dbSNP:rs373044722)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077270" FT VARIANT 500 FT /note="H -> P (in GACI1)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077271" FT VARIANT 504 FT /note="S -> R (in GACI1; decreased nucleotide FT phosphodiesterase activity; no effect on localization to FT plasma membrane)" FT /evidence="ECO:0000269|PubMed:20016754, FT ECO:0000269|PubMed:27467858" FT /id="VAR_077272" FT VARIANT 513 FT /note="Y -> C (in GACI1; loss of nucleotide FT phosphodiesterase activity; no effect on localization to FT plasma membrane; dbSNP:rs1243920034)" FT /evidence="ECO:0000269|PubMed:20016754, FT ECO:0000269|PubMed:27467858" FT /id="VAR_077273" FT VARIANT 538 FT /note="D -> H (in GACI1; loss of nucleotide FT phosphodiesterase activity; no effect on localization to FT plasma membrane; dbSNP:rs387906673)" FT /evidence="ECO:0000269|PubMed:22209248, FT ECO:0000269|PubMed:27467858" FT /id="VAR_067913" FT VARIANT 570 FT /note="Y -> C (in GACI1; dbSNP:rs140248167)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077274" FT VARIANT 579 FT /note="L -> F (in GACI1; uncertain significance; FT dbSNP:rs121918024)" FT /evidence="ECO:0000269|PubMed:12881724, FT ECO:0000269|PubMed:20016754" FT /id="VAR_018514" FT VARIANT 586 FT /note="G -> R (in GACI1; loss of nucleotide FT phosphodiesterase activity; loss of localization to plasma FT membrane; dbSNP:rs777367269)" FT /evidence="ECO:0000269|PubMed:22209248, FT ECO:0000269|PubMed:27467858" FT /id="VAR_067914" FT VARIANT 611 FT /note="L -> V (in dbSNP:rs79079368)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077275" FT VARIANT 659 FT /note="Y -> C (in GACI1; decreased nucleotide FT phosphodiesterase activity; no effect on localization to FT plasma membrane; dbSNP:rs143393727)" FT /evidence="ECO:0000269|PubMed:20016754, FT ECO:0000269|PubMed:27467858" FT /id="VAR_077276" FT VARIANT 668 FT /note="E -> K (no effect on nucleotide phosphodiesterase FT activity; no effect on localization to plasma membrane; FT dbSNP:rs115371819)" FT /evidence="ECO:0000269|PubMed:20016754, FT ECO:0000269|PubMed:27467858" FT /id="VAR_077277" FT VARIANT 726 FT /note="C -> R (in GACI1)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077278" FT VARIANT 774 FT /note="R -> C (decreased nucleotide phosphodiesterase FT activity; no effect on localization to plasma membrane; FT dbSNP:rs28933977)" FT /evidence="ECO:0000269|PubMed:12881724, FT ECO:0000269|PubMed:15605415, ECO:0000269|PubMed:20016754, FT ECO:0000269|PubMed:27467858" FT /id="VAR_018515" FT VARIANT 777 FT /note="H -> R (in GACI1; decreased nucleotide FT phosphodiesterase activity; no effect on localization to FT plasma membrane; dbSNP:rs147346173)" FT /evidence="ECO:0000269|PubMed:20016754, FT ECO:0000269|PubMed:27467858" FT /id="VAR_077279" FT VARIANT 779 FT /note="T -> P (in dbSNP:rs1805138)" FT /evidence="ECO:0000269|PubMed:10453738" FT /id="VAR_014144" FT VARIANT 792 FT /note="N -> S (in ARHR2 and GACI1; dbSNP:rs370184526)" FT /evidence="ECO:0000269|PubMed:20016754, FT ECO:0000269|PubMed:25741938" FT /id="VAR_077280" FT VARIANT 804 FT /note="D -> H (in GACI1)" FT /evidence="ECO:0000269|PubMed:20016754" FT /id="VAR_077281" FT VARIANT 821 FT /note="R -> H (decreased nucleotide phosphodiesterase FT activity; no effect on localization to plasma membrane; FT dbSNP:rs367759638)" FT /evidence="ECO:0000269|PubMed:20016754, FT ECO:0000269|PubMed:27467858" FT /id="VAR_077282" FT VARIANT 886 FT /note="R -> T (in dbSNP:rs8192683)" FT /id="VAR_037435" FT VARIANT 888 FT /note="R -> W (in GACI1; loss of nucleotide FT phosphodiesterase activity; loss of localization to plasma FT membrane; dbSNP:rs184483616)" FT /evidence="ECO:0000269|PubMed:20016754, FT ECO:0000269|PubMed:27467858" FT /id="VAR_077283" FT VARIANT 901 FT /note="Y -> S (in ARHR2; loss of activity; FT dbSNP:rs121908249)" FT /evidence="ECO:0000269|PubMed:20137772" FT /id="VAR_063720" FT TURN 151..155 FT /evidence="ECO:0007829|PDB:2YS0" FT STRAND 163..165 FT /evidence="ECO:0007829|PDB:2YS0" FT HELIX 168..173 FT /evidence="ECO:0007829|PDB:2YS0" FT HELIX 180..183 FT /evidence="ECO:0007829|PDB:2YS0" SQ SEQUENCE 925 AA; 104924 MW; 0ECAA063801CAFEB CRC64; MERDGCAGGG SRGGEGGRAP REGPAGNGRD RGRSHAAEAP GDPQAAASLL APMDVGEEPL EKAARARTAK DPNTYKVLSL VLSVCVLTTI LGCIFGLKPS CAKEVKSCKG RCFERTFGNC RCDAACVELG NCCLDYQETC IEPEHIWTCN KFRCGEKRLT RSLCACSDDC KDKGDCCINY SSVCQGEKSW VEEPCESINE PQCPAGFETP PTLLFSLDGF RAEYLHTWGG LLPVISKLKK CGTYTKNMRP VYPTKTFPNH YSIVTGLYPE SHGIIDNKMY DPKMNASFSL KSKEKFNPEW YKGEPIWVTA KYQGLKSGTF FWPGSDVEIN GIFPDIYKMY NGSVPFEERI LAVLQWLQLP KDERPHFYTL YLEEPDSSGH SYGPVSSEVI KALQRVDGMV GMLMDGLKEL NLHRCLNLIL ISDHGMEQGS CKKYIYLNKY LGDVKNIKVI YGPAARLRPS DVPDKYYSFN YEGIARNLSC REPNQHFKPY LKHFLPKRLH FAKSDRIEPL TFYLDPQWQL ALNPSERKYC GSGFHGSDNV FSNMQALFVG YGPGFKHGIE ADTFENIEVY NLMCDLLNLT PAPNNGTHGS LNHLLKNPVY TPKHPKEVHP LVQCPFTRNP RDNLGCSCNP SILPIEDFQT QFNLTVAEEK IIKHETLPYG RPRVLQKENT ICLLSQHQFM SGYSQDILMP LWTSYTVDRN DSFSTEDFSN CLYQDFRIPL SPVHKCSFYK NNTKVSYGFL SPPQLNKNSS GIYSEALLTT NIVPMYQSFQ VIWRYFHDTL LRKYAEERNG VNVVSGPVFD FDYDGRCDSL ENLRQKRRVI RNQEILIPTH FFIVLTSCKD TSQTPLHCEN LDTLAFILPH RTDNSESCVH GKHDSSWVEE LLMLHRARIT DVEHITGLSF YQQRKEPVSD ILKLKTHLPT FSQED //