P21589 (5NTD_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
5'-nucleotidase
Short name=5'-NT
EC=3.1.3.5

Alternative name(s):
Ecto-5'-nucleotidase
CD_antigen=CD73

Gene names

Name:	NT5E
Synonyms:	NT5, NTE

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	574 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Hydrolyzes extracellular nucleotides into membrane permeable nucleosides. Exhibits AMP-, NAD-, and NMN-nucleosidase activities. Ref.9
Catalytic activity	A 5'-ribonucleotide + H2O = a ribonucleoside + phosphate.
Cofactor	Zinc.
Subunit structure	Homodimer. Ref.10
Subcellular location	Cell membrane; Lipid-anchor › GPI-anchor Ref.1.
Involvement in disease	Calcification of joints and arteries (CALJA) [MIM:211800]: A condition characterized by adult-onset calcification of the lower extremity arteries, including the iliac, femoral and tibial arteries, and hand and foot capsule joints. Age of onset has been reported as early as the second decade of life, usually involving intense joint pain or calcification in the hands. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.11
Sequence similarities	Belongs to the 5'-nucleotidase family.

Ontologies

Keywords
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Signal
Ligand	Metal-binding Nucleotide-binding Zinc
Molecular function	Hydrolase
PTM	Disulfide bond GPI-anchor Glycoprotein Lipoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	AMP catabolic process Inferred from electronic annotation. Source: Compara DNA metabolic process Traceable author statement Ref.1. Source: ProtInc adenosine biosynthetic process Inferred from electronic annotation. Source: Compara negative regulation of inflammatory response Inferred from electronic annotation. Source: Compara purine nucleobase metabolic process Traceable author statement. Source: Reactome purine nucleotide catabolic process Traceable author statement. Source: Reactome pyrimidine nucleobase metabolic process Traceable author statement. Source: Reactome pyrimidine nucleoside catabolic process Traceable author statement. Source: Reactome
Cellular_component	anchored to membrane Inferred from electronic annotation. Source: UniProtKB-KW cytoplasm Inferred from direct assay. Source: HPA extracellular vesicular exosome Inferred from direct assay PubMed 21362503. Source: UniProtKB plasma membrane Inferred from direct assay. Source: HPA
Molecular_function	5'-nucleotidase activity Inferred from experiment. Source: Reactome metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW nucleotide binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P21589-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P21589-2)

The sequence of this isoform differs from the canonical sequence as follows:
     404-453: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 26

26

Ref.6

Chain

27 – 549

523

5'-nucleotidase Ref.1

PRO_0000000015

Propeptide

550 – 574

25

Removed in mature form

PRO_0000000016

Regions

Region

500 – 506

7

Substrate binding

Sites

Metal binding

36

1

Zinc 1

Metal binding

38

1

Zinc 1

Metal binding

85

1

Zinc 1

Metal binding

85

1

Zinc 2

Metal binding

117

1

Zinc 2

Metal binding

220

1

Zinc 2

Metal binding

243

1

Zinc 2

Binding site

245

1

Substrate

Binding site

354

1

Substrate

Binding site

390

1

Substrate

Binding site

395

1

Substrate

Binding site

417

1

Substrate

Site

118

1

Transition state stabilizer

Site

121

1

Transition state stabilizer Probable

Amino acid modifications

Lipidation

549

1

GPI-anchor amidated serine Ref.1

Glycosylation

53

1

N-linked (GlcNAc...) Potential

Glycosylation

311

1

N-linked (GlcNAc...) Ref.7 Ref.10

Glycosylation

333

1

N-linked (GlcNAc...) Ref.7 Ref.8

Glycosylation

403

1

N-linked (GlcNAc...) Ref.7

Disulfide bond

51 ↔ 57

Ref.10

Disulfide bond

353 ↔ 358

Ref.10

Disulfide bond

365 ↔ 387

Ref.10

Disulfide bond

476 ↔ 479

Ref.10

Natural variations

Alternative sequence

404 – 453

50

Missing in isoform 2.

VSP_043076

Natural variant

358

1

C → Y in CALJA. Ref.11

VAR_065185

Natural variant

376

1

T → A. Ref.5
Corresponds to variant rs2229523 [ dbSNP | Ensembl ].

VAR_022091

Natural variant

379

1

M → T.
Corresponds to variant rs2229524 [ dbSNP | Ensembl ].

VAR_048103

Secondary structure

1

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574

Helix Strand Turn

Details...

Beta strand

27 – 34

8

Beta strand

48 – 50

3

Helix

54 – 56

3

Helix

61 – 74

14

Beta strand

76 – 82

7

Beta strand

87 – 90

4

Helix

91 – 96

6

Helix

99 – 108

10

Beta strand

111 – 114

4

Helix

117 – 120

4

Helix

123 – 128

6

Turn

129 – 134

6

Beta strand

142 – 146

5

Helix

150 – 154

5

Turn

155 – 157

3

Beta strand

158 – 166

9

Beta strand

169 – 177

9

Helix

181 – 184

4

Beta strand

189 – 193

5

Helix

196 – 209

14

Beta strand

215 – 221

7

Helix

223 – 232

10

Beta strand

238 – 240

3

Beta strand

250 – 252

3

Beta strand

254 – 256

3

Beta strand

263 – 268

6

Beta strand

274 – 278

5

Beta strand

285 – 294

10

Beta strand

300 – 305

6

Helix

318 – 335

18

Beta strand

337 – 344

8

Helix

350 – 353

4

Helix

359 – 371

13

Helix

379 – 381

3

Beta strand

386 – 390

5

Helix

391 – 393

3

Turn

401 – 404

4

Beta strand

405 – 407

3

Helix

408 – 414

7

Beta strand

420 – 427

8

Helix

428 – 439

12

Turn

440 – 443

4

Beta strand

450 – 459

10

Beta strand

469 – 475

7

Beta strand

477 – 481

5

Beta strand

484 – 486

3

Beta strand

492 – 498

7

Helix

499 – 502

4

Helix

505 – 507

3

Helix

509 – 514

6

Beta strand

516 – 523

8

Helix

524 – 535

12

Beta strand

536 – 538

3

Beta strand

544 – 548

5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 1, 1991. Version 1. Checksum: A99AF170AB7EAECE	FASTA	574	63,368
	10 20 30 40 50 60 MCPRAARAPA TLLLALGAVL WPAAGAWELT ILHTNDVHSR LEQTSEDSSK CVNASRCMGG 70 80 90 100 110 120 VARLFTKVQQ IRRAEPNVLL LDAGDQYQGT IWFTVYKGAE VAHFMNALRY DAMALGNHEF 130 140 150 160 170 180 DNGVEGLIEP LLKEAKFPIL SANIKAKGPL ASQISGLYLP YKVLPVGDEV VGIVGYTSKE 190 200 210 220 230 240 TPFLSNPGTN LVFEDEITAL QPEVDKLKTL NVNKIIALGH SGFEMDKLIA QKVRGVDVVV 250 260 270 280 290 300 GGHSNTFLYT GNPPSKEVPA GKYPFIVTSD DGRKVPVVQA YAFGKYLGYL KIEFDERGNV 310 320 330 340 350 360 ISSHGNPILL NSSIPEDPSI KADINKWRIK LDNYSTQELG KTIVYLDGSS QSCRFRECNM 370 380 390 400 410 420 GNLICDAMIN NNLRHTDEMF WNHVSMCILN GGGIRSPIDE RNNGTITWEN LAAVLPFGGT 430 440 450 460 470 480 FDLVQLKGST LKKAFEHSVH RYGQSTGEFL QVGGIHVVYD LSRKPGDRVV KLDVLCTKCR 490 500 510 520 530 540 VPSYDPLKMD EVYKVILPNF LANGGDGFQM IKDELLRHDS GDQDINVVST YISKMKVIYP 550 560 570 AVEGRIKFST GSHCHGSFSL IFLSLWAVIF VLYQ
	Isoform 2 [UniParc]. Checksum: 98A11D22CFC7C610	FASTA	524	57,949
	10 20 30 40 50 60 MCPRAARAPA TLLLALGAVL WPAAGAWELT ILHTNDVHSR LEQTSEDSSK CVNASRCMGG 70 80 90 100 110 120 VARLFTKVQQ IRRAEPNVLL LDAGDQYQGT IWFTVYKGAE VAHFMNALRY DAMALGNHEF 130 140 150 160 170 180 DNGVEGLIEP LLKEAKFPIL SANIKAKGPL ASQISGLYLP YKVLPVGDEV VGIVGYTSKE 190 200 210 220 230 240 TPFLSNPGTN LVFEDEITAL QPEVDKLKTL NVNKIIALGH SGFEMDKLIA QKVRGVDVVV 250 260 270 280 290 300 GGHSNTFLYT GNPPSKEVPA GKYPFIVTSD DGRKVPVVQA YAFGKYLGYL KIEFDERGNV 310 320 330 340 350 360 ISSHGNPILL NSSIPEDPSI KADINKWRIK LDNYSTQELG KTIVYLDGSS QSCRFRECNM 370 380 390 400 410 420 GNLICDAMIN NNLRHTDEMF WNHVSMCILN GGGIRSPIDE RNNGIHVVYD LSRKPGDRVV 430 440 450 460 470 480 KLDVLCTKCR VPSYDPLKMD EVYKVILPNF LANGGDGFQM IKDELLRHDS GDQDINVVST 490 500 510 520 YISKMKVIYP AVEGRIKFST GSHCHGSFSL IFLSLWAVIF VLYQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Primary structure of human placental 5'-nucleotidase and identification of the glycolipid anchor in the mature form." Misumi Y., Ogata S., Ohkubo K., Hirose S., Ikehara Y. Eur. J. Biochem. 191:563-569(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, GPI-ANCHOR AT SER-549. Tissue: Placenta.
[2]	"Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries." Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J., Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S., Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y. , Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S., Isogai T. DNA Res. 12:117-126(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
[3]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"Isolation and characterization of the promoter of the human 5'-nucleotidase (CD73)-encoding gene." Hansen K.R., Resta R., Webb C.F., Thompson L.F. Gene 167:307-312(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-113. Tissue: Placenta.
[5]	Zanoni L., Rosi F., Pagani R., Marinello E. Submitted (MAY-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 359-489, VARIANT ALA-376. Tissue: Leukocyte.
[6]	"Characterization of soluble vs membrane-bound human placental 5'-nucleotidase." Klemens M.R., Sherman W.R., Holmberg N.J., Ruedi J.M., Low M.G., Thompson L.F. Biochem. Biophys. Res. Commun. 172:1371-1377(1990) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 27-40. Tissue: Placenta.
[7]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-311; ASN-333 AND ASN-403, MASS SPECTROMETRY. Tissue: Liver.
[8]	"Mass-spectrometric identification and relative quantification of N-linked cell surface glycoproteins." Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., Schiess R., Aebersold R., Watts J.D. Nat. Biotechnol. 27:378-386(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-333, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[9]	"The high-resolution crystal structure of periplasmic Haemophilus influenzae NAD nucleotidase reveals a novel enzymatic function of human CD73 related to NAD metabolism." Garavaglia S., Bruzzone S., Cassani C., Canella L., Allegrone G., Sturla L., Mannino E., Millo E., De Flora A., Rizzi M. Biochem. J. 441:131-141(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBSTRATE SPECIFICITY.
[10]	"Crystal structure of the human ecto-5'-nucleotidase (CD73): insights into the regulation of purinergic signaling." Knapp K., Zebisch M., Pippel J., El-Tayeb A., Muller C.E., Strater N. Structure 20:2161-2173(2012) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 27-549 IN COMPLEXES WITH ATP ANALOG AND ZINC IONS, SUBUNIT, GLYCOSYLATION AT ASN-311, DISULFIDE BONDS.
[11]	"NT5E mutations and arterial calcifications." St Hilaire C., Ziegler S.G., Markello T.C., Brusco A., Groden C., Gill F., Carlson-Donohoe H., Lederman R.J., Chen M.Y., Yang D., Siegenthaler M.P., Arduino C., Mancini C., Freudenthal B., Stanescu H.C., Zdebik A.A., Chaganti R.K., Nussbaum R.L. , Kleta R., Gahl W.A., Boehm M. N. Engl. J. Med. 364:432-442(2011) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CALJA TYR-358.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X55740 mRNA. Translation: CAA39271.1.
AK075008 mRNA. Translation: BAG52050.1.
AL135903, AL589666 Genomic DNA. Translation: CAH72337.1.
AL589666, AL135903 Genomic DNA. Translation: CAI40168.1.
U21730 Genomic DNA. Translation: AAA96950.1.
AF069067 Genomic DNA. Translation: AAC98672.1.

IPI

IPI00009456.
IPI00552302.

PIR

S11032.

RefSeq

NP_001191742.1. NM_001204813.1.
NP_002517.1. NM_002526.3.

UniGene

Hs.153952.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
4H1S	X-ray	2.20	A/B	27-549	[»]
4H1Y	X-ray	1.58	P	27-549	[»]
4H2B	X-ray	1.70	A	27-549	[»]
4H2F	X-ray	1.85	A	27-549	[»]
4H2G	X-ray	1.55	A	27-549	[»]
4H2I	X-ray	2.00	A	27-549	[»]

ProteinModelPortal

P21589.

ModBase

Search...

Protein-protein interaction databases

MINT

MINT-5002487.

STRING

9606.ENSP00000257770.

PTM databases

PhosphoSite

P21589.

Polymorphism databases

DMDM

112825.

Proteomic databases

PaxDb

P21589.

PRIDE

P21589.

Protocols and materials databases

DNASU

4907.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000257770; ENSP00000257770; ENSG00000135318.
ENST00000369651; ENSP00000358665; ENSG00000135318.

GeneID

4907.

KEGG

hsa:4907.

UCSC

uc003pko.4. human.
uc010kbr.3. human.

Organism-specific databases

CTD

4907.

GeneCards

GC06P086216.

HGNC

HGNC:8021. NT5E.

HPA

HPA017357.

MIM

129190. gene.
211800. phenotype.

neXtProt

NX_P21589.

Orphanet

289601. Hereditary arterial and articular multiple calcification syndrome.

PharmGKB

PA31804.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0737.

HOGENOM

HOG000247215.

HOVERGEN

HBG000026.

InParanoid

P21589.

KO

K01081.

OMA

GHTHQSY.

OrthoDB

EOG4TMR1Q.

PhylomeDB

P21589.

Enzyme and pathway databases

BioCyc

MetaCyc:HS05981-MONOMER.

Pathway_Interaction_DB

hif1_tfpathway. HIF-1-alpha transcription factor network.

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

P21589.

Bgee

P21589.

CleanEx

HS_NT5E.

Genevestigator

P21589.

GermOnline

ENSG00000135318. Homo sapiens.

Family and domain databases

Gene3D

3.90.780.10. 1 hit.

InterPro

IPR008334. 5'-Nucleotdase_C.
IPR006146. 5'-Nucleotdase_CS.
IPR006179. 5_nucleotidase/apyrase.
IPR004843. Metallo_PEstase_dom.
[Graphical view]

PANTHER

PTHR11575. PTHR11575. 1 hit.

Pfam

PF02872. 5_nucleotid_C. 1 hit.
PF00149. Metallophos. 1 hit.
[Graphical view]

PRINTS

PR01607. APYRASEFAMLY.

SUPFAM

SSF55816. 5'-Nucleotdase_C. 1 hit.

PROSITE

PS00785. 5_NUCLEOTIDASE_1. 1 hit.
PS00786. 5_NUCLEOTIDASE_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChEMBL

CHEMBL5957.

ChiTaRS

NT5E. human.

DrugBank

DB00806. Pentoxifylline.

GenomeRNAi

4907.

NextBio

18883.

SOURCE

Search...

Entry information

Entry name

5NTD_HUMAN

Accession

Primary (citable) accession number: P21589
Secondary accession number(s): B3KQI8, O75520, Q5W116

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 1, 1991
Last sequence update:	May 1, 1991
Last modified:	May 29, 2013
This is version 145 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.