ENPP1

Protein identityUniProt · HPA

UniProt accession

P22413

Gene

ENPP1

Ensembl

ENSG00000197594

Chromosome

6

Canonical length

925 aa

Protein class

CD markers, Disease related genes, Enzymes, Human disease related genes, Metabolic proteins, Potential drug targets, Predicted membrane proteins, Predicted secreted proteins

Secretome location

Secreted - unknown location

Quaternary structure

Homodimer

OverviewNCBI Gene

This gene is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein comprising two identical disulfide-bonded subunits. This protein has broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. This protein may function to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates. Mutations in this gene have been associated with 'idiopathic' infantile arterial calcification, ossification of the posterior longitudinal ligament of the spine (OPLL), and insulin resistance. [provided by RefSeq, Jul 2008]

Canonical amino-acid sequenceUniProt

925 residues, UniProt reviewed canonical sequence.

>P22413|ENPP1
     1  MERDGCAGGG SRGGEGGRAP REGPAGNGRD RGRSHAAEAP GDPQAAASLL APMDVGEEPL
    61  EKAARARTAK DPNTYKVLSL VLSVCVLTTI LGCIFGLKPS CAKEVKSCKG RCFERTFGNC
   121  RCDAACVELG NCCLDYQETC IEPEHIWTCN KFRCGEKRLT RSLCACSDDC KDKGDCCINY
   181  SSVCQGEKSW VEEPCESINE PQCPAGFETP PTLLFSLDGF RAEYLHTWGG LLPVISKLKK
   241  CGTYTKNMRP VYPTKTFPNH YSIVTGLYPE SHGIIDNKMY DPKMNASFSL KSKEKFNPEW
   301  YKGEPIWVTA KYQGLKSGTF FWPGSDVEIN GIFPDIYKMY NGSVPFEERI LAVLQWLQLP
   361  KDERPHFYTL YLEEPDSSGH SYGPVSSEVI KALQRVDGMV GMLMDGLKEL NLHRCLNLIL
   421  ISDHGMEQGS CKKYIYLNKY LGDVKNIKVI YGPAARLRPS DVPDKYYSFN YEGIARNLSC
   481  REPNQHFKPY LKHFLPKRLH FAKSDRIEPL TFYLDPQWQL ALNPSERKYC GSGFHGSDNV
   541  FSNMQALFVG YGPGFKHGIE ADTFENIEVY NLMCDLLNLT PAPNNGTHGS LNHLLKNPVY
   601  TPKHPKEVHP LVQCPFTRNP RDNLGCSCNP SILPIEDFQT QFNLTVAEEK IIKHETLPYG
   661  RPRVLQKENT ICLLSQHQFM SGYSQDILMP LWTSYTVDRN DSFSTEDFSN CLYQDFRIPL
   721  SPVHKCSFYK NNTKVSYGFL SPPQLNKNSS GIYSEALLTT NIVPMYQSFQ VIWRYFHDTL
   781  LRKYAEERNG VNVVSGPVFD FDYDGRCDSL ENLRQKRRVI RNQEILIPTH FFIVLTSCKD
   841  TSQTPLHCEN LDTLAFILPH RTDNSESCVH GKHDSSWVEE LLMLHRARIT DVEHITGLSF
   901  YQQRKEPVSD ILKLKTHLPT FSQED

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against ENPP1 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Cell surface

Secreted

No

Transmembrane segments

1

Mean surface accessibility (rSASA)

0.26

Highest tissue expression

41 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about ENPP1.

Disease | AllUniProt

Conditions ENPP1 is implicated in, by any mechanism.

• Ossification of the posterior longitudinal ligament of the spine (OPLL) MIM:602475
• Arterial calcification of infancy, generalized, 1 (GACI1) MIM:208000
• Type 2 diabetes mellitus (T2D) MIM:125853
• Hypophosphatemic rickets, autosomal recessive, 2 (ARHR2) MIM:613312
• Cole disease (COLED) MIM:615522

Disease | GeneticClinVar

100 pathogenic / likely-pathogenic of 935 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Arterial calcification, generalized, of infancy, 1
• Hypophosphatemic rickets, autosomal recessive, 2
• Hypopigmentation-punctate palmoplantar keratoderma syndrome
• Type 2 diabetes mellitus
• Inherited obesity

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.59

gnomAD pLI

0

gnomAD missense Z

1.62

DepMap mean gene effect

0.03

DepMap dependency class

none

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 3% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• 3'-phosphoadenosine 5'-phosphosulfate metabolic process
• ATP metabolic process
• bone mineralization
• cellular response to insulin stimulus
• gene expression
• generation of precursor metabolites and energy
• immune response
• inorganic diphosphate transport
• intracellular phosphate ion homeostasis
• melanocyte differentiation
• negative regulation of bone mineralization
• negative regulation of cell growth
• negative regulation of D-glucose import
• negative regulation of fat cell differentiation
• negative regulation of glycogen biosynthetic process
• negative regulation of insulin receptor signaling pathway
• nucleic acid metabolic process
• nucleoside triphosphate catabolic process
• phosphate ion homeostasis
• phosphate-containing compound metabolic process
• regulation of bone mineralization
• response to ATP
• negative regulation of hh target transcription factor activity

Molecular functions

• 3',5'-cyclic-AMP phosphodiesterase activity
• 3'-phosphoadenosine 5'-phosphosulfate binding
• ATP binding
• ATP diphosphatase activity
• calcium ion binding
• cyclic-GMP-AMP hydrolase activity
• exonuclease activity
• GTP diphosphatase activity
• insulin receptor binding
• nucleic acid binding
• nucleoside triphosphate diphosphatase activity
• phosphatase activity
• phosphodiesterase I activity
• polysaccharide binding
• protein homodimerization activity
• scavenger receptor activity
• UTP diphosphatase activity
• zinc ion binding
• dinucleotide phosphatase activity

Cellular components

• basolateral plasma membrane
• cell surface
• extracellular space
• lysosomal membrane
• membrane
• plasma membrane

Protein domainsUniProt · Pfam · InterPro

• Somatomedin B domain
• DNA/RNA non-specific endonuclease/pyrophosphatase/phosphodiesterase domain
• Type I phosphodiesterase/nucleotide pyrophosphatase/phosphate transferase
• Alkaline-phosphatase-like, core domain superfamily
• Somatomedin B domain, chordata
• ENPP1-3/EXOG-like, endonuclease/phosphodiesterase domain
• Somatomedin B-like domain superfamily
• His-Me finger superfamily
• DNA/RNA non-specific endonuclease superfamily
• Somatomedin B domain
• DNA/RNA non-specific endonuclease
• Type I phosphodiesterase / nucleotide pyrophosphatase

KeywordsUniProt

• Biomineralization
• Calcium
• Cell membrane
• Diabetes mellitus
• Disulfide bond
• Glycoprotein
• Hydrolase
• Membrane
• Metal-binding
• Obesity
• Phosphoprotein
• Repeat
• Secreted
• Signal-anchor
• Transmembrane
• Transmembrane helix
• Zinc

InteractionsUniProt · HPA

Protein binding partners of ENPP1 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• INSR