ENPP1_HUMAN
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 03-AUG-2022, entry version 224.
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},
GN PC1 {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 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 [20]
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 [21]
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 [22]
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 [23]
RP VARIANT GLN-173, AND INVOLVEMENT IN NIDDM.
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 [24]
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 [25]
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 [26]
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 [27]
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 [28]
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 [29]
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 [30]
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 [31]
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 [32]
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 [33]
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 [34]
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 [35]
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 [36]
RP VARIANT GLN-173, AND INVOLVEMENT IN NIDDM.
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 May also be involved in the regulation of the availability of
CC nucleotide sugars in the endoplasmic reticulum and Golgi, and the
CC regulation of purinergic signaling (PubMed:27467858, PubMed:8001561).
CC Inhibits ectopic joint calcification and maintains articular
CC chondrocytes by repressing hedgehog signaling; it is however unclear
CC whether hedgehog inhibition is direct or indirect (By similarity).
CC Appears to modulate insulin sensitivity and function (PubMed:10615944).
CC Also involved in melanogenesis (PubMed:28964717). Also able to
CC hydrolyze 2',3'-cGAMP (cyclic GMP-AMP), a second messenger that
CC 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:8001561,
CC 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};
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 -!- 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: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]:
CC A multifactorial disorder of glucose homeostasis caused by a lack of
CC sensitivity to the body's own insulin. Affected individuals usually
CC have an obese body habitus and manifestations of a metabolic syndrome
CC characterized by diabetes, insulin resistance, hypertension and
CC hypertriglyceridemia. The disease results in long-term complications
CC that affect the eyes, kidneys, nerves, and blood vessels.
CC {ECO:0000269|PubMed:16186408, ECO:0000269|PubMed:29958952}.
CC Note=Disease susceptibility is associated with variants affecting the
CC 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};
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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 PDBsum; 2YS0; -.
DR PDBsum; 6WET; -.
DR PDBsum; 6WEU; -.
DR PDBsum; 6WEV; -.
DR PDBsum; 6WEW; -.
DR PDBsum; 6WFJ; -.
DR AlphaFoldDB; P22413; -.
DR BMRB; P22413; -.
DR SMR; P22413; -.
DR BioGRID; 111193; 47.
DR IntAct; P22413; 13.
DR MINT; P22413; -.
DR STRING; 9606.ENSP00000354238; -.
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 GlyGen; P22413; 10 sites, 18 N-linked glycans (2 sites), 1 O-linked glycan (1 site).
DR iPTMnet; P22413; -.
DR PhosphoSitePlus; P22413; -.
DR BioMuta; ENPP1; -.
DR DMDM; 23503088; -.
DR EPD; P22413; -.
DR jPOST; P22413; -.
DR MassIVE; P22413; -.
DR MaxQB; P22413; -.
DR PaxDb; P22413; -.
DR PeptideAtlas; P22413; -.
DR PRIDE; P22413; -.
DR ProteomicsDB; 53988; -.
DR Antibodypedia; 32916; 413 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 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; PMYPSFQ; -.
DR OrthoDB; 999163at2759; -.
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; 10 hits in 1078 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 163 other tissues.
DR ExpressionAtlas; P22413; baseline and differential.
DR Genevisible; P22413; HS.
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:0016021; C:integral component of membrane; ISS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; HDA: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:0036218; F:dTTP diphosphatase activity; IEA:UniProtKB-EC.
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:0035529; F:NADH pyrophosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0003676; F:nucleic acid binding; IEA:InterPro.
DR GO; GO:0047429; F:nucleoside-triphosphate diphosphatase activity; IDA:UniProtKB.
DR GO; GO:0004551; F:nucleotide diphosphatase activity; IDA:BHF-UCL.
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:0110148; P:biomineralization; IDA:MGI.
DR GO; GO:0030282; P:bone mineralization; IDA:MGI.
DR GO; GO:0030643; P:cellular phosphate ion homeostasis; IDA:BHF-UCL.
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: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:0090305; P:nucleic acid phosphodiester bond hydrolysis; 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 Gene3D; 3.40.570.10; -; 1.
DR Gene3D; 3.40.720.10; -; 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; IPR029890; ENPP1.
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:SF77; PTHR10151:SF77; 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; SSF53649; 1.
DR SUPFAM; SSF54060; SSF54060; 1.
DR SUPFAM; SSF90188; SSF90188; 2.
DR PROSITE; PS00524; SMB_1; 2.
DR PROSITE; PS50958; SMB_2; 2.
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 NIDDM; 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; unknown pathological 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; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:25741938"
FT /id="VAR_077263"
FT VARIANT 242
FT /note="G -> E (in GACI1; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:20016754"
FT /id="VAR_077264"
FT VARIANT 250
FT /note="P -> L (in GACI1; unknown pathological 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; unknown pathological 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; unknown pathological significance;
FT dbSNP:rs764735802)"
FT /evidence="ECO:0000269|PubMed:20016754"
FT /id="VAR_077267"
FT VARIANT 371
FT /note="Y -> F (in GACI1; unknown pathological 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; unknown pathological 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; unknown pathological 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
