Reviewed, UniProtKB/Swiss-Prot P15144 (AMPN_HUMAN)

Names and origin

Protein names

Recommended name:
    Aminopeptidase N
      Short name=hAPN
    EC=3.4.11.2
Alternative name(s):
    Alanyl aminopeptidase
    Microsomal aminopeptidase
    Aminopeptidase M
    gp150
    Myeloid plasma membrane glycoprotein CD13
    CD_antigen=CD13

Gene names

Name:	ANPEP
Synonyms:	APN, CD13, PEPN

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	967 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	Broad specificity aminopeptidase. Plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. May play a critical role in the pathogenesis of cholesterol gallstone disease. May be involved in the metabolism of regulatory peptides of diverse cell types including small intestinal and tubular epithelial cells, macrophages, granulocytes and synaptic membranes from the CNS. Found to cleave antigen peptides bound to major histocompatibility complex class II molecules of presenting cells and to degrade neurotransmitters at synaptic junctions. Is also implicated as a regulator of IL-8 bioavailability in the endometrium, and therefore may contribute to the regulation of angiogenesis. Is used as a marker for acute myeloid leukemia and plays a role in tumor invasion. In case of human coronavirus 229E (HCoV-229E) infection, serves as receptor for HCoV-229E spike glycoprotein. Mediates as well human cytomegalovirus (HCMV) infection.
Catalytic activity	Release of an N-terminal amino acid, Xaa-|-Yaa- from a peptide, amide or arylamide. Xaa is preferably Ala, but may be most amino acids including Pro (slow action). When a terminal hydrophobic residue is followed by a prolyl residue, the two may be released as an intact Xaa-Pro dipeptide.
Cofactor	Binds 1 zinc ion per subunit By similarity.
Subunit structure	Homodimer. Interacts with the S1 domain of HCoV-229E spike protein.
Subcellular location	Cell membrane; Single-pass type II membrane protein. Cytoplasm › cytosolPotential. Note= A soluble form has also been detected.
Tissue specificity	Expressed in epithelial cells of the kidney, intestine, and respiratory tract; granulocytes, monocytes, fibroblasts, endothelial cells, cerebral pericytes at the blood-brain barrier, synaptic membranes of cells in the CNS. Also expressed in endometrial stromal cells, but not in the endometrial glandular cells. Found in the vasculature of tissues that undergo angiogenesis and in malignant gliomas and lymph node metastases from multiple tumor types but not in blood vessels of normal tissues. A soluble form has been found in plasma. It is found to be elevated in plasma and effusions of cancer patients.
Induction	Estradiol and IL-8 decrease enzymatic activity in vitro in endometrial stromal cells by 40% and 30%, respectively.
Domain	Amino acids 260-353 are essential to mediate susceptibility to infection with HCoV-229E (in porcine/human chimeric studies) and more specifically amino acids 288-295 (mutagenesis studies).
Post-translational modification	Sulfated By similarity. N- and O-glycosylated. May undergo proteolysis and give rise to a soluble form.
Involvement in disease	Defects in ANPEP may be a cause of various types of leukemia or lymphoma.
Miscellaneous	Found to serve as a receptor for tumor-homing peptides, more specifically NGR peptides. It could serve thus as a target for delivering drugs into tumors. Concentration in human hepatic bile, varies from 17.3 to 57.6 micrograms/ml.
Sequence similarities	Belongs to the peptidase M1 family.

Ontologies

Keywords
Biological process	Angiogenesis Differentiation Host-virus interaction
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Polymorphism
Domain	Signal-anchor Transmembrane
Ligand	Metal-binding Zinc
Molecular function	Aminopeptidase Developmental protein Hydrolase Metalloprotease Protease
PTM	Glycoprotein Phosphoprotein Sulfation
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW proteolysis Inferred from electronic annotation. Source: InterPro
Cellular component	ER-Golgi intermediate compartment Inferred from direct assay. Source: UniProtKB integral to plasma membrane Ref.2 Traceable author statement. Source: ProtInc
Molecular function	aminopeptidase activity Traceable author statement. Source: ProtInc metallopeptidase activity Ref.2 Traceable author statement. Source: ProtInc receptor activity Ref.11 Traceable author statement. Source: ProtInc zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed
	Chain	2 – 967	966	Aminopeptidase N		PRO_0000095081
Regions
	Topological domain	2 – 8	7	Cytoplasmic
	Transmembrane	9 – 32	24	Signal-anchor for type II membrane protein Potential
	Region	33 – 68	36	Cytosolic Ser/Thr-rich junction
	Region	69 – 967	899	Metalloprotease
	Region	260 – 353	94	Interaction with HCoV-229E
Sites
	Active site	389	1	By similarity
	Active site	477	1	Proton donor Potential
	Metal binding	388	1	Zinc; catalytic By similarity
	Metal binding	392	1	Zinc; catalytic By similarity
	Metal binding	411	1	Zinc; catalytic By similarity
Amino acid modifications
	Modified residue	176	1	Sulfotyrosine Potential
	Modified residue	419	1	Sulfotyrosine Potential
	Modified residue	424	1	Sulfotyrosine Potential
	Modified residue	913	1	Sulfotyrosine Potential
	Modified residue	928	1	Phosphothreonine
	Glycosylation	128	1	N-linked (GlcNAc...)
	Glycosylation	234	1	N-linked (GlcNAc...)
	Glycosylation	265	1	N-linked (GlcNAc...)
	Glycosylation	319	1	N-linked (GlcNAc...) Potential
	Glycosylation	527	1	N-linked (GlcNAc...) Potential
	Glycosylation	573	1	N-linked (GlcNAc...) Potential
	Glycosylation	625	1	N-linked (GlcNAc...) Potential
	Glycosylation	681	1	N-linked (GlcNAc...)
	Glycosylation	735	1	N-linked (GlcNAc...) Potential
	Glycosylation	818	1	N-linked (GlcNAc...)
Natural variations
	Natural variant	20	1	V → M: dbSNP rs10152474.		VAR_031262
	Natural variant	86	1	R → Q: dbSNP rs25653.		VAR_014736
	Natural variant	242	1	D → Y		VAR_006727
	Natural variant	243	1	L → P		VAR_006728
	Natural variant	311	1	A → V: dbSNP rs17240268.		VAR_031263
	Natural variant	321	1	T → M: dbSNP rs8179199.		VAR_031264
	Natural variant	603	1	I → K: dbSNP rs17240212.		VAR_031265
	Natural variant	603	1	I → M: dbSNP rs8192297.		VAR_031266
	Natural variant	752	1	S → N: dbSNP rs25651.		VAR_014737
Experimental info
	Mutagenesis	288 – 295	8	DYVEKQAS → QSVEETAQ: No change in receptor activity and HCoV-229E infection
	Mutagenesis	288 – 295	8	DYVEKQAS → QSVNEQAQ: No change in receptor activity and HCoV-229E infection
	Mutagenesis	288 – 295	8	DYVEKQAS → QSVNETAQ: Complete loss of receptor activity and blocks HCoV-229E infection. No loss of enzymatic activity
	Mutagenesis	291 – 293	3	EKQ → NKT: Complete loss of receptor activity and blocks HCoV-229E infection. No loss of enzymatic activity
	Mutagenesis	291	1	E → N: No change of receptor activity and HCoV-229E infection
	Mutagenesis	293	1	Q → T: No change of receptor activity and HCoV-229E infection
	Mutagenesis	818	1	N → E: Very low receptor activity and HCoV-229E infection
	Sequence conflict	536	1	V → E in CAA31640. Ref.1
	Sequence conflict	887	1	L → P in CAA31640. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P15144-1 [UniParc]. Last modified April 3, 2007. Version 4. Checksum: 37B6BC1BF0D6B1F2	FASTA	967	109,540
	10 20 30 40 50 60 MAKGFYISKS LGILGILLGV AAVCTIIALS VVYSQEKNKN ANSSPVASTT PSASATTNPA 70 80 90 100 110 120 SATTLDQSKA WNRYRLPNTL KPDSYRVTLR PYLTPNDRGL YVFKGSSTVR FTCKEATDVI 130 140 150 160 170 180 IIHSKKLNYT LSQGHRVVLR GVGGSQPPDI DKTELVEPTE YLVVHLKGSL VKDSQYEMDS 190 200 210 220 230 240 EFEGELADDL AGFYRSEYME GNVRKVVATT QMQAADARKS FPCFDEPAMK AEFNITLIHP 250 260 270 280 290 300 KDLTALSNML PKGPSTPLPE DPNWNVTEFH TTPKMSTYLL AFIVSEFDYV EKQASNGVLI 310 320 330 340 350 360 RIWARPSAIA AGHGDYALNV TGPILNFFAG HYDTPYPLPK SDQIGLPDFN AGAMENWGLV 370 380 390 400 410 420 TYRENSLLFD PLSSSSSNKE RVVTVIAHEL AHQWFGNLVT IEWWNDLWLN EGFASYVEYL 430 440 450 460 470 480 GADYAEPTWN LKDLMVLNDV YRVMAVDALA SSHPLSTPAS EINTPAQISE LFDAISYSKG 490 500 510 520 530 540 ASVLRMLSSF LSEDVFKQGL ASYLHTFAYQ NTIYLNLWDH LQEAVNNRSI QLPTTVRDIM 550 560 570 580 590 600 NRWTLQMGFP VITVDTSTGT LSQEHFLLDP DSNVTRPSEF NYVWIVPITS IRDGRQQQDY 610 620 630 640 650 660 WLIDVRAQND LFSTSGNEWV LLNLNVTGYY RVNYDEENWR KIQTQLQRDH SAIPVINRAQ 670 680 690 700 710 720 IINDAFNLAS AHKVPVTLAL NNTLFLIEER QYMPWEAALS SLSYFKLMFD RSEVYGPMKN 730 740 750 760 770 780 YLKKQVTPLF IHFRNNTNNW REIPENLMDQ YSEVNAISTA CSNGVPECEE MVSGLFKQWM 790 800 810 820 830 840 ENPNNNPIHP NLRSTVYCNA IAQGGEEEWD FAWEQFRNAT LVNEADKLRA ALACSKELWI 850 860 870 880 890 900 LNRYLSYTLN PDLIRKQDAT STIISITNNV IGQGLVWDFV QSNWKKLFND YGGGSFSFSN 910 920 930 940 950 960 LIQAVTRRFS TEYELQQLEQ FKKDNEETGF GSGTRALEQA LEKTKANIKW VKENKEVVLQ WFTENSK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Complete amino acid sequence of human intestinal aminopeptidase N as deduced from cloned cDNA." Olsen J., Cowell G.M., Koenigshoefer E., Danielsen E.M., Moeller J., Laustsen L., Hansen O.C., Welinder K.G., Engberg J., Hunziker W., Spiess M., Sjoestroem H., Noren O. FEBS Lett. 238:307-314(1988) [PubMed: 2901990] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS GLN-86 AND MET-603. Tissue: Intestine.
[2]	"Human myeloid plasma membrane glycoprotein CD13 (gp150) is identical to aminopeptidase N." Look A.T., Ashmun R.A., Shapiro L.H., Peiper S.C. J. Clin. Invest. 83:1299-1307(1989) [PubMed: 2564851] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 2-21, VARIANT GLN-86.
[3]	"Analysis of the DNA sequence and duplication history of human chromosome 15." Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., Abouelleil A. , Arachchi H.M., Baradarani L., Birditt B., Bloom S., Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C. Nature 440:671-675(2006) [PubMed: 16572171] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Pancreas.
[5]	"Separate promoters control transcription of the human aminopeptidase N gene in myeloid and intestinal epithelial cells." Shapiro L.H., Ashmun R.A., Roberts W.M., Look A.T. J. Biol. Chem. 266:11999-12007(1991) [PubMed: 1675638] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-15. Tissue: Intestinal epithelium.
[6]	"Genomic organisation of aminopeptidase N." Eiz-Vesper B., Fuchs N., Gottschalk D., Mueller K., Reuter S., Blasczyk R. Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-479 AND 524-967, VARIANT GLN-86. Tissue: Peripheral blood.
[7]	"Identification of an alanine aminopeptidase in human maternal serum as a membrane-bound aminopeptidase N." Watanabe Y., Iwaki-Egawa S., Mizukoshi H., Fujimoto Y. Biol. Chem. Hoppe-Seyler 376:397-400(1995) [PubMed: 7576235] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-20 AND 70-81.
[8]	"Cholesterol crystallization-promoting activity of aminopeptidase-N isolated from the vesicular carrier of biliary lipids." Nunez L., Amigo L., Rigotti A., Puglielli L., Mingrone G., Greco A.V., Nervi F. FEBS Lett. 329:84-88(1993) [PubMed: 8102610] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-18.
[9]	"Purification and characterization of aminopeptidase N from human plasma." Tokioka-Terao M., Hiwada K., Kokubu T. Enzyme 32:65-75(1984) [PubMed: 6149934] [Abstract] Cited for: CHARACTERIZATION, SUBUNIT.
[10]	"Variable O-glycosylation of CD13 (aminopeptidase N)." O'Connell P.J., Gerkis V., d'Apice A.J.F. J. Biol. Chem. 266:4593-4597(1991) [PubMed: 1705556] [Abstract] Cited for: GLYCOSYLATION.
[11]	"Human aminopeptidase N is a receptor for human coronavirus 229E." Yeager C.L., Ashmun R.A., Williams R.K., Cardellichio C.B., Shapiro L.H., Look A.T., Holmes K.V. Nature 357:420-422(1992) [PubMed: 1350662] [Abstract] Cited for: INTERACTION WITH HCOV-229E SPIKE GLYCOPROTEIN, CHARACTERIZATION OF HCOV-229E RECEPTOR FUNCTION.
[12]	"CD13 (GP150; aminopeptidase-N): predominant functional activity in blood is localized to plasma and is not cell-surface associated." Favaloro E.J., Browning T., Facey D. Exp. Hematol. 21:1695-1701(1993) [PubMed: 7902291] [Abstract] Cited for: IDENTIFICATION OF SOLUBLE FORM.
[13]	"CD13 (human aminopeptidase N) mediates human cytomegalovirus infection." Soderberg C., Giugni T.D., Zaia J.A., Larsson S., Wahlberg J.M., Moller E. J. Virol. 67:6576-6585(1993) [PubMed: 8105105] [Abstract] Cited for: CHARACTERIZATION OF CMV RECEPTOR FUNCTION.
[14]	"Characterization of functional domains in the human coronavirus HCV 229E receptor." Kolb A.F., Maile J., Heister A., Siddell S.G. J. Gen. Virol. 77:2515-2521(1996) [PubMed: 8887485] [Abstract] Cited for: IDENTIFICATION OF RECEPTOR FUNCTIONAL DOMAINS FOR HCOV-229E INFECTION.
[15]	"Defectively N-glycosylated and non-O-glycosylated aminopeptidase N (CD13) is normally expressed at the cell surface and has full enzymatic activity." Noren K., Hansen G.H., Clausen H., Noren O., Sjostrom H., Vogel L.K. Exp. Cell Res. 231:112-118(1997) [PubMed: 9056417] [Abstract] Cited for: FUNCTION, GLYCOSYLATION.
[16]	"Identification of residues critical for the human coronavirus 229E receptor function of human aminopeptidase N." Kolb A.F., Hegyi A., Siddell S.G. J. Gen. Virol. 78:2795-2802(1997) [PubMed: 9367365] [Abstract] Cited for: IDENTIFICATION OF RESIDUES CRITICAL FOR HCOV-229E INFECTION.
[17]	"Characterization of determinants involved in the feline infectious peritonitis virus receptor function of feline aminopeptidase N." Hegyi A., Kolb A.F. J. Gen. Virol. 79:1387-1391(1998) [PubMed: 9634079] [Abstract] Cited for: IDENTIFICATION OF RECEPTOR FUNCTIONAL DOMAINS FOR TGEV INFECTION.
[18]	"Modification of the amino terminus of a class II epitope confers resistance to degradation by CD13 on dendritic cells and enhances presentation to T cells." Dong X., An B., Salvucci Kierstead L., Storkus W.J., Amoscato A.A., Salter R.D. J. Immunol. 164:129-135(2000) [PubMed: 10605003] [Abstract] Cited for: FUNCTION, ENZYMATIC CLEAVAGE OF ANTIGEN PEPTIDES BOUND TO CLASS II MHC.
[19]	"Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis." Pasqualini R., Koivunen E., Kain R., Lahdenranta J., Sakamoto M., Stryhn A., Ashmun R.A., Shapiro L.H., Arap W., Ruoslahti E. Cancer Res. 60:722-727(2000) [PubMed: 10676659] [Abstract] Cited for: ROLE IN ANGIOGENESIS, CHARACTERIZATION OF RECEPTOR FOR TUMOR-HOMING PEPTIDES FUNCTION.
[20]	"Expression of aminopeptidase N in human endometrium and regulation of its activity by estrogen." Seli E., Senturk L.M., Bahtiyar O.M., Kayisli U.A., Arici A. Fertil. Steril. 75:1172-1176(2001) [PubMed: 11384645] [Abstract] Cited for: FUNCTION, INDUCTION BY ESTRADIOL AND IL-8.
[21]	"Molecular determinants of species specificity in the coronavirus receptor aminopeptidase N (CD13): influence of N-linked glycosylation." Wentworth D.E., Holmes K.V. J. Virol. 75:9741-9752(2001) [PubMed: 11559807] [Abstract] Cited for: MUTAGENESIS OF 288-ASP--SER-295 AND ASN-818.
[22]	"Soluble aminopeptidase N/CD13 in malignant and nonmalignant effusions and intratumoral fluid." van Hensbergen Y., Broxterman H.J., Hanemaaijer R., Jorna A.S., van Lent N.A., Verheul H.M., Pinedo H.M., Hoekman K. Clin. Cancer Res. 8:3747-3754(2002) [PubMed: 12473585] [Abstract] Cited for: FUNCTION OF SOLUBLE FORM.
[23]	"Identification of a receptor-binding domain of the spike glycoprotein of human coronavirus HCoV-229E." Bonavia A., Zelus B.D., Wentworth D.E., Talbot P.J., Holmes K.V. J. Virol. 77:2530-2538(2003) [PubMed: 12551991] [Abstract] Cited for: INTERACTION WITH HCOV-229E SPIKE GLYCOPROTEIN.
[24]	"A proteomic analysis of human bile." Kristiansen T.Z., Bunkenborg J., Gronborg M., Molina H., Thuluvath P.J., Argani P., Goggins M.G., Maitra A., Pandey A. Mol. Cell. Proteomics 3:715-728(2004) [PubMed: 15084671] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-265, MASS SPECTROMETRY. Tissue: Bile.
[25]	"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry." Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D. J. Proteome Res. 4:2070-2080(2005) [PubMed: 16335952] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-128; ASN-234; ASN-265; ASN-681 AND ASN-818, MASS SPECTROMETRY. Tissue: Plasma.
[26]	"Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra." Yu L.-R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D. J. Proteome Res. 6:4150-4162(2007) [PubMed: 17924679] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-928, MASS SPECTROMETRY. Tissue: Epithelium.
[27]	"Identification of point mutations in the aminopeptidase N gene by SSCP analysis and sequencing." Lendeckel U., Wex T., Arndt M., Frank K., Franke A., Ansorge S. Hum. Mutat. Suppl. 1:S158-S160(1998) [PubMed: 9452074] [Abstract] Cited for: VARIANTS TYR-242 AND PRO-243.
+	Additional computationally mapped references.