Reviewed, UniProtKB/Swiss-Prot P78310 (CXAR_HUMAN)

Names and origin

Protein names

Recommended name:
    Coxsackievirus and adenovirus receptor
Alternative name(s):
    Coxsackievirus B-adenovirus receptor
    HCVADR
      Short name=hCAR
    CVB3-binding protein

Gene names

Name:	CXADR
Synonyms:	CAR

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	365 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	Component of the epithelial apical junction complex that is essential for the tight junction integrity. Proposed to function as a homophilic cell adhesion molecule. Recruits MPDZ to intercellular contact sites. Probably involved in transepithelial migration of polymorphonuclear leukocytes (PMN) through adhesive interactions with AMICA1/JAML located in the plasma membrane of PMN. Receptor for group B coxsackieviruses and subgroup C of adenoviruses (AD2 and AD5), susceptibility to infection is correlated to its level of expression and availability at the plasma membrane of cells.
Subunit structure	Monomer. Probably homodimer formed by 2 molecules on adjacent cells. Interacts with LNX, MPDZ, BAIAP1, DLG4, PRKCABP, TJP1 and CTNNB1. Secreted isoform 3, isoform 4 and isoform 5 can interact with the extracellular domain of the receptor. Binds adenovirus 12 fiber protein. Isoform 5 but not isoform 3 binds to coxsackievirus.
Subcellular location	Isoform 1: Cell membrane; Single-pass type I membrane protein. Cell junction › tight junction. Cell junction › adherens junction. Basolateral cell membrane; Single-pass type I membrane protein. Note= In epithelial cells localizes to the apical junction complex composced of tight and adherens junctions. In airway epithelial cells localized to basolateral membrane but not to apical surface. Isoform 2: Cell membrane; Single-pass type I membrane protein. Cell junction › tight junction. Cell junction › adherens junction. Basolateral cell membrane; Single-pass membrane protein. Note= In epithelial cells localizes to the apical junction complex composced of tight and adherens junctions. In airway epithelial cells localized to basolateral membrane but not to apical surface. Isoform 3: Secreted. Isoform 4: Secreted. Isoform 5: Secreted.
Tissue specificity	Expressed in pancreas, brain, heart, small intestine, testis, prostate and at a lower level in liver and lung. Isoform 5 is ubiquitoulsy expressed while isoform 3 is expressed in heart, lung and pancreas. In skeletal muscle, isoform 1 is found at the neuromuscular junction and isoform 2 is found in blood vessels. In cardiac muscle, isoform 1 and isoform 2 are found at intercalated disks. In heart expressed in subendothelial layers of the vessel wall but not in the luminal endothelial surface. Expression is elevated in hearts with dilated cardiomyopathy.
Domain	The Ig-like C2-type 1 domain probably mediates homodimerization and interaction with JAML. The PDZ-binding motif mediates interaction with MPDZ and BAIAP1.
Post-translational modification	N-glycosylated By similarity. Palmitoylated on Cys-259 and/or Cys-260; required for proper localization to the plasma membrane.
Sequence similarities	Contains 2 Ig-like C2-type (immunoglobulin-like) domains.

Ontologies

Keywords
Biological process	Cell adhesion Host-virus interaction
Cellular component	Cell junction Cell membrane Membrane Secreted Tight junction
Coding sequence diversity	Alternative splicing
Domain	Immunoglobulin domain Repeat Signal Transmembrane
Molecular function	Receptor
PTM	Glycoprotein Lipoprotein Palmitate Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	cell adhesion Inferred from electronic annotation. Source: UniProtKB-KW interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	Golgi apparatus Inferred from direct assay. Source: HPA basolateral plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell extracellular region Inferred from electronic annotation. Source: UniProtKB-KW integral to plasma membrane Ref.1 Traceable author statement. Source: ProtInc tight junction Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	protein binding Inferred from electronic annotation. Source: UniProtKB-KW receptor activity Ref.2 Traceable author statement. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 5 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P78310-1) Also known as: SIV; 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.
Notes: In epithelial cells localizes to the apical junction complex composced of tight and adherens junctions. In airway epithelial cells localized to basolateral membrane but not to apical surface.
Isoform 2 (identifier: P78310-2) Also known as: CAR2; HCAR2; TVV; The sequence of this isoform differs from the canonical sequence as follows:      340-345: VAAPNL → FKYPY      346-365: Missing.
Notes: In epithelial cells localizes to the apical junction complex composced of tight and adherens junctions. In airway epithelial cells localized to basolateral membrane but not to apical surface.
Sequence annotation (Features)
	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
	Sequence conflict	343	1	P → A in AAD31772. Ref.10
Isoform 3 (identifier: P78310-3) Also known as: CAR2/7; Gamma; The sequence of this isoform differs from the canonical sequence as follows:      71-89: IILYSGDKIYDDYYPDLKG → GRCATSKEPYVHCQKLHRQ      90-365: Missing.
Isoform 4 (identifier: P78310-4) Also known as: CAR3/7; The sequence of this isoform differs from the canonical sequence as follows:      139-139: V → GKMCHLQRAVRPLPEATSAVIIHPWGPCLLPTWKDIPRLSITKYQVKTLNALLRVRLSHLLR      140-365: Missing.
Isoform 5 (identifier: P78310-5) Also known as: CAR4/7; Beta; The sequence of this isoform differs from the canonical sequence as follows:      191-191: E → GKMCHLQRAVRPLPEATSAVIIHPWGPCLLPTWKDIPRLSITKYQVKTLNALLRVRLSHLLR      192-365: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 19

19

Potential

Chain

20 – 365

346

Coxsackievirus and adenovirus receptor

PRO_0000014739

Regions

Topological domain

20 – 237

218

Extracellular Potential

Transmembrane

238 – 258

21

Potential

Topological domain

259 – 365

107

Cytoplasmic Potential

Domain

20 – 134

115

Ig-like C2-type 1

Domain

141 – 228

88

Ig-like C2-type 2

Motif

360 – 365

6

PDZ-binding

Amino acid modifications

Modified residue

293

1

Phosphoserine By similarity

Modified residue

300

1

Phosphoserine By similarity

Modified residue

306

1

Phosphoserine

Modified residue

323

1

Phosphoserine By similarity

Modified residue

332

1

Phosphoserine

Lipidation

259

1

S-palmitoyl cysteine Probable

Lipidation

260

1

S-palmitoyl cysteine Probable

Glycosylation

106

1

N-linked (GlcNAc...) Potential

Glycosylation

201

1

N-linked (GlcNAc...) Potential

Disulfide bond

41 ↔ 120

Disulfide bond

162 ↔ 212

By similarity

Natural variations

Alternative sequence

71 – 89

19

IILYS…PDLKG → GRCATSKEPYVHCQKLHRQ in isoform 3.

VSP_014819

Alternative sequence

90 – 365

276

Missing in isoform 3.

VSP_014820

Alternative sequence

139

1

V → GKMCHLQRAVRPLPEATSAV IIHPWGPCLLPTWKDIPRLS ITKYQVKTLNALLRVRLSHL LR in isoform 4.

VSP_014821

Alternative sequence

140 – 365

226

Missing in isoform 4.

VSP_014822

Alternative sequence

191

1

E → GKMCHLQRAVRPLPEATSAV IIHPWGPCLLPTWKDIPRLS ITKYQVKTLNALLRVRLSHL LR in isoform 5.

VSP_014823

Alternative sequence

192 – 365

174

Missing in isoform 5.

VSP_014824

Alternative sequence

340 – 345

6

VAAPNL → FKYPY in isoform 2.

VSP_014825

Alternative sequence

346 – 365

20

Missing in isoform 2.

VSP_014826

Experimental info

Mutagenesis

70 – 72

3

VII → AID: Abolishes binding to adenovirus type 5

Mutagenesis

259 – 260

2

CC → AA: Loss of palmitoylation and altered localization

Mutagenesis

318

1

Y → A: Affects basolateral localization in airway epithelial cells

Mutagenesis

345 – 348

4

LSRM → AAAA: Affects basolateral localization in airway epithelial cells

Secondary structure

1

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365

Helix Strand Turn

Details...

Beta strand

21 – 32

12

Beta strand

37 – 39

3

Beta strand

42 – 44

3

Beta strand

53 – 61

9

Beta strand

68 – 75

8

Beta strand

78 – 80

3

Turn

86 – 90

5

Beta strand

91 – 93

3

Helix

98 – 100

3

Beta strand

105 – 107

3

Helix

112 – 114

3

Beta strand

116 – 124

9

Beta strand

127 – 138

12

Beta strand

145 – 148

4

Beta strand

156 – 163

8

Beta strand

166 – 168

3

Beta strand

171 – 178

8

Helix

185 – 192

8

Beta strand

195 – 201

7

Beta strand

208 – 215

8

Beta strand

221 – 227

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (SIV) [UniParc]. Last modified May 1, 1997. Version 1. Checksum: AB01C6346CB7FE64	FASTA	365	40,030
	10 20 30 40 50 60 MALLLCFVLL CGVVDFARSL SITTPEEMIE KAKGETAYLP CKFTLSPEDQ GPLDIEWLIS 70 80 90 100 110 120 PADNQKVDQV IILYSGDKIY DDYYPDLKGR VHFTSNDLKS GDASINVTNL QLSDIGTYQC 130 140 150 160 170 180 KVKKAPGVAN KKIHLVVLVK PSGARCYVDG SEEIGSDFKI KCEPKEGSLP LQYEWQKLSD 190 200 210 220 230 240 SQKMPTSWLA EMTSSVISVK NASSEYSGTY SCTVRNRVGS DQCLLRLNVV PPSNKAGLIA 250 260 270 280 290 300 GAIIGTLLAL ALIGLIIFCC RKKRREEKYE KEVHHDIRED VPPPKSRTST ARSYIGSNHS 310 320 330 340 350 360 SLGSMSPSNM EGYSKTQYNQ VPSEDFERTP QSPTLPPAKV AAPNLSRMGA IPVMIPAQSK DGSIV
	Isoform 2 (CAR2) (HCAR2) (TVV) [UniParc]. Checksum: EEE9C22E96C697AA		344	38,124
	10 20 30 40 50 60 MALLLCFVLL CGVVDFARSL SITTPEEMIE KAKGETAYLP CKFTLSPEDQ GPLDIEWLIS 70 80 90 100 110 120 PADNQKVDQV IILYSGDKIY DDYYPDLKGR VHFTSNDLKS GDASINVTNL QLSDIGTYQC 130 140 150 160 170 180 KVKKAPGVAN KKIHLVVLVK PSGARCYVDG SEEIGSDFKI KCEPKEGSLP LQYEWQKLSD 190 200 210 220 230 240 SQKMPTSWLA EMTSSVISVK NASSEYSGTY SCTVRNRVGS DQCLLRLNVV PPSNKAGLIA 250 260 270 280 290 300 GAIIGTLLAL ALIGLIIFCC RKKRREEKYE KEVHHDIRED VPPPKSRTST ARSYIGSNHS 310 320 330 340 SLGSMSPSNM EGYSKTQYNQ VPSEDFERTP QSPTLPPAKF KYPY
	Isoform 3 (CAR2/7) (Gamma) [UniParc]. Checksum: 50951EAAC77CAE36		89	9,967
	10 20 30 40 50 60 MALLLCFVLL CGVVDFARSL SITTPEEMIE KAKGETAYLP CKFTLSPEDQ GPLDIEWLIS 70 80 PADNQKVDQV GRCATSKEPY VHCQKLHRQ
	Isoform 4 (CAR3/7) [UniParc]. Checksum: 43FDB19DF6A7FEB8		200	22,370
	10 20 30 40 50 60 MALLLCFVLL CGVVDFARSL SITTPEEMIE KAKGETAYLP CKFTLSPEDQ GPLDIEWLIS 70 80 90 100 110 120 PADNQKVDQV IILYSGDKIY DDYYPDLKGR VHFTSNDLKS GDASINVTNL QLSDIGTYQC 130 140 150 160 170 180 KVKKAPGVAN KKIHLVVLGK MCHLQRAVRP LPEATSAVII HPWGPCLLPT WKDIPRLSIT 190 200 KYQVKTLNAL LRVRLSHLLR
	Isoform 5 (CAR4/7) (Beta) [UniParc]. Checksum: 4532559D01AB67E2		252	28,201
	10 20 30 40 50 60 MALLLCFVLL CGVVDFARSL SITTPEEMIE KAKGETAYLP CKFTLSPEDQ GPLDIEWLIS 70 80 90 100 110 120 PADNQKVDQV IILYSGDKIY DDYYPDLKGR VHFTSNDLKS GDASINVTNL QLSDIGTYQC 130 140 150 160 170 180 KVKKAPGVAN KKIHLVVLVK PSGARCYVDG SEEIGSDFKI KCEPKEGSLP LQYEWQKLSD 190 200 210 220 230 240 SQKMPTSWLA GKMCHLQRAV RPLPEATSAV IIHPWGPCLL PTWKDIPRLS ITKYQVKTLN 250 ALLRVRLSHL LR

References

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[1]	"HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses." Tomko R.P., Xu R., Philipson L. Proc. Natl. Acad. Sci. U.S.A. 94:3352-3356(1997) [PubMed: 9096397] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION AS A VIRUS RECEPTOR, TISSUE SPECIFICITY.
[2]	"Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5." Bergelson J.M., Cunningham J.A., Droguett G., Kurt-Jones E., Krithivas A., Hong J.S., Horwitz M.S., Crowell R.L., Finberg R.W. Science 275:1320-1323(1997) [PubMed: 9036860] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]	"Genomic organization and chromosomal localization of the human Coxsackievirus B-adenovirus receptor gene." Bowles K.R., Gibson J., Wu J., Shaffer L.G., Towbin J.A., Bowles N.E. Hum. Genet. 105:354-359(1999) [PubMed: 10543405] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Interaction of coxsackievirus B3 with the full length coxsackievirus-adenovirus receptor." He Y., Chipman P.R., Howitt J., Bator C.M., Whitt M.A., Baker T.S., Kuhn R.J., Anderson C.W., Freimuth P., Rossmann M.G. Nat. Struct. Biol. 8:874-878(2001) [PubMed: 11573093] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"Alternatively spliced soluble coxsackie-adenovirus receptors inhibit coxsackievirus infection." Doerner A., Xiong D., Couch K., Yajima T., Knowlton K.U. J. Biol. Chem. 279:18497-18503(2004) [PubMed: 14978041] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3; 4 AND 5), INTERACTION WITH COXSACKIEVIRUS TYPE B3, SUBCELLULAR LOCATION.
[6]	"Putative regulatory domains in the human and mouse CAR genes." Andersson B., Tomko R.P., Andersson K., Darban H., Oncu D., Mizra M., Sollerbrant K., Sonnhammer E., Philipson L. Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]	"Full-length cDNA libraries and normalization." Li W.B., Gruber C., Jessee J., Polayes D. Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Cervix.
[8]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[9]	"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] (ISOFORM 1). Tissue: Cervix.
[10]	"Expression of Coxsackie-adenovirus-receptor and alpha v-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers." Fechner H., Haack A., Wang H., Wang X., Eizema K., Pauschinger M., Schoemaker R.G., van Veghel R., Houtsmuller A.B., Schultheiss H.-P., Lamers J.M.J., Poller W. Gene Ther. 6:1520-1535(1999) [