Reviewed, UniProtKB/Swiss-Prot P41181 (AQP2_HUMAN)

Names and origin

Protein names

Recommended name:
    Aquaporin-2
      Short name=AQP-2
Alternative name(s):
    Aquaporin-CD
      Short name=AQP-CD
    Water channel protein for renal collecting duct
    ADH water channel
    Collecting duct water channel protein
    WCH-CD

Gene names

Name:

AQP2

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	271 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Forms a water-specific channel that provides the plasma membranes of renal collecting duct with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient.
Subcellular location	Apical cell membrane; Multi-pass membrane protein. Cytoplasmic vesicle membrane; Multi-pass membrane protein. Note: Shuttles from vesicles to the apical membrane. Ref.7
Tissue specificity	Expressed in renal collecting tubules.
Domain	Aquaporins contain two tandem repeats each containing three membrane-spanning domains and a pore-forming loop with the signature motif Asn-Pro-Ala (NPA).
Post-translational modification	Ser-256 phosphorylation is necessary and sufficient for expression at the apical membrane. Endocytosis is not phosphorylation-dependent.
Involvement in disease	Defects in AQP2 are the cause of diabetes insipidus nephrogenic autosomal (ANDI) [MIM:125800]; also known as diabetes insipidus nephrogenic type 2. ANDI is caused by the inability of the renal collecting ducts to absorb water in response to arginine vasopressin. It is characterized by excessive water drinking (polydypsia), excessive urine excretion (polyuria), persistent hypotonic urine, and hypokalemia. Inheritance can be autosomal dominant or recessive. Ref.3 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17
Sequence similarities	Belongs to the MIP/aquaporin (TC 1.A.8) family. [View classification]

Ontologies

Keywords
Biological process	Transport
Cellular component	Cell membrane Cytoplasmic vesicle Membrane
Coding sequence diversity	Polymorphism
Disease	Diabetes insipidus Disease mutation
Domain	Repeat Transmembrane
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	excretion Traceable author statement. Source: ProtInc transmembrane transport Inferred from electronic annotation. Source: InterPro
Cellular component	apical plasma membrane Inferred from direct assay. Source: UniProtKB cytoplasmic vesicle Inferred from electronic annotation. Source: UniProtKB-KW integral to membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	water channel activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 271	271	Aquaporin-2		PRO_0000063934
Regions
	Topological domain	1 – 16	16	Cytoplasmic Potential
	Transmembrane	17 – 34	18	Potential
	Topological domain	35 – 40	6	Extracellular Potential
	Transmembrane	41 – 59	19	Potential
	Topological domain	60 – 85	26	Cytoplasmic Potential
	Transmembrane	86 – 107	22	Potential
	Topological domain	108 – 127	20	Extracellular Potential
	Transmembrane	128 – 148	21	Potential
	Topological domain	149 – 156	8	Cytoplasmic Potential
	Transmembrane	157 – 176	20	Potential
	Topological domain	177 – 202	26	Extracellular Potential
	Transmembrane	203 – 224	22	Potential
	Topological domain	225 – 271	47	Cytoplasmic Potential
	Motif	68 – 70	3	NPA 1
	Motif	184 – 186	3	NPA 2
Amino acid modifications
	Modified residue	256	1	Phosphoserine; by PKA Ref.7
	Modified residue	261	1	Phosphoserine By similarity
	Modified residue	264	1	Phosphoserine By similarity
	Glycosylation	123	1	N-linked (GlcNAc...) Potential
Natural variations
	Natural variant	22	1	L → V in ANDI. Ref.9		VAR_015239
	Natural variant	28	1	L → P in ANDI. Ref.15		VAR_015240
	Natural variant	47	1	A → V in ANDI. Ref.15		VAR_015241
	Natural variant	57	1	Q → P in ANDI. dbSNP rs28931580. Ref.16		VAR_015256
	Natural variant	64	1	G → R in ANDI. Ref.3		VAR_004401
	Natural variant	68	1	N → S in ANDI. Ref.10		VAR_015242
	Natural variant	71	1	V → M in ANDI. Ref.15		VAR_015243
	Natural variant	100	1	G → V in ANDI. dbSNP rs28929477.		VAR_015257
	Natural variant	121	1	L → F: dbSNP rs11169226.		VAR_037577
	Natural variant	125	1	T → M in ANDI. Ref.12 Ref.14 Ref.15		VAR_015244
	Natural variant	126	1	T → M in ANDI. Ref.10		VAR_015245
	Natural variant	147	1	A → T in ANDI. Ref.10		VAR_015246
	Natural variant	168	1	V → M in ANDI. Ref.11		VAR_015247
	Natural variant	175	1	G → R in ANDI. Ref.12 Ref.14 Ref.15		VAR_015248
	Natural variant	181	1	C → W in ANDI. Ref.9		VAR_015249
	Natural variant	185	1	P → A in ANDI. Ref.15		VAR_015250
	Natural variant	187	1	R → C in ANDI; mutant protein does not fold properly and is not functional. Ref.3 Ref.17		VAR_004402
	Natural variant	190	1	A → T in ANDI; mutant protein does not fold properly and is not functional. Ref.12 Ref.17		VAR_015251
	Natural variant	194	1	V → I		VAR_015252
	Natural variant	202	1	W → C in ANDI. Ref.8		VAR_015253
	Natural variant	216	1	S → P in ANDI. Ref.3 Ref.11		VAR_004403
	Natural variant	258	1	E → K in ANDI; retained in the Golgi compartment. Ref.13		VAR_015254
	Natural variant	262	1	P → L in ANDI; mutant protein folds properly and is functional but is retained in intracellular vesicles and does not localize to the ER; upon coexpression with wild-type AQP2 mutant protein interacts with wild-type AQP2 and the resulting heterotetramer properly localizes to the apical membrane. Ref.12 Ref.17		VAR_015255
Experimental info
	Mutagenesis	148	1	S → A: No effect on sorting from the ER to the vesicles, redistribution to apical membrane, or endocytosis. Ref.7
	Mutagenesis	148	1	S → D: Retained in the endoplasmic reticulum. Ref.7
	Mutagenesis	229	1	S → A: No effect on sorting from the ER to the vesicles, redistribution to apical membrane, or endocytosis. Ref.7
	Mutagenesis	229	1	S → D: No effect on sorting from the ER to the vesicles, redistribution to apical membrane, or endocytosis. Ref.7
	Mutagenesis	231	1	S → A: No effect on sorting from the ER to the vesicles, redistribution to apical membrane, or endocytosis. Ref.7
	Mutagenesis	231	1	S → D: No effect on sorting from the ER to the vesicles, redistribution to apical membrane, or endocytosis. Ref.7
	Mutagenesis	244	1	T → A: No effect on sorting from the ER to the vesicles, redistribution to apical membrane, or endocytosis. Ref.7
	Mutagenesis	244	1	T → E: No effect on sorting from the ER to the vesicles, redistribution to apical membrane, or endocytosis. Ref.7
	Mutagenesis	256	1	S → A: Retained in vesicles. Ref.7
	Mutagenesis	256	1	S → D: Expressed in the apical membrane. Ref.7
	Sequence conflict	35 – 38	4	PQAL → ATAP Ref.4
	Sequence conflict	83	1	V → F Ref.4

Sequences

	Sequence		Length	Mass (Da)
	P41181-1 [UniParc]. Last modified February 1, 1995. Version 1. Checksum: C2DDE2AF4DDD192A	FASTA	271	28,837
	10 20 30 40 50 60 MWELRSIAFS RAVFAEFLAT LLFVFFGLGS ALNWPQALPS VLQIAMAFGL GIGTLVQALG 70 80 90 100 110 120 HISGAHINPA VTVACLVGCH VSVLRAAFYV AAQLLGAVAG AALLHEITPA DIRGDLAVNA 130 140 150 160 170 180 LSNSTTAGQA VTVELFLTLQ LVLCIFASTD ERRGENPGTP ALSIGFSVAL GHLLGIHYTG 190 200 210 220 230 240 CSMNPARSLA PAVVTGKFDD HWVFWIGPLV GAILGSLLYN YVLFPPAKSL SERLAVLKGL 250 260 270 EPDTDWEERE VRRRQSVELH SPQSLPRGTK A

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Requirement of human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine." Deen P.M.T., Verdijk M.A.J., Knoers V.V.A.M., Wieringa B., Monnens L.A.H., van Os C.H., van Oost B.A. Science 264:92-94(1994) [PubMed: 8140421] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Isolation of human aquaporin-CD gene." Uchida S., Sasaki S., Fushimi K., Marumo F. J. Biol. Chem. 269:23451-23455(1994) [PubMed: 7522228] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene." van Lieburg A.F., Verdijk M.A.J., Knoers V.V.A.M., van Essen A.J., Proesmans W., Mallmann R., Monnens L.A.H., van Oost B.A., van Os C.H., Deen P.M.T. Am. J. Hum. Genet. 55:648-652(1994) [PubMed: 7524315] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS ANDI ARG-64; CYS-187 AND PRO-216.
[4]	"Cloning, characterization, and chromosomal mapping of human aquaporin of collecting duct." Sasaki S., Fushimi K., Saito H., Saito F., Uchida S., Ishibashi K., Kuwahara M., Ikeuchi T., Inui K., Nakajima K. J. Clin. Invest. 93:1250-1256(1994) [PubMed: 7510718] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Kidney.
[5]	"Heteroligomerization of an aquaporin-2 mutant with wild-type aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus." Marr N., Bichet D.G., Lonergan M., Arthus M.-F., Jeck N., Seyberth H.W., Rosenthal W., van Os C.H., Oksche A., Deen P.M.T. Hum. Mol. Genet. 11:779-789(2002) [PubMed: 11929850] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Kidney.
[6]	"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: Colon.
[7]	"The role of putative phosphorylation sites in the targeting and shuttling of the aquaporin-2 water channel." van Balkom B.W.M., Savelkoul P.J.M., Markovich D., Hofman E., Nielsen S., van der Sluijs P., Deen P.M.T. J. Biol. Chem. 277:41473-41479(2002) [PubMed: 12194985] [Abstract] Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-256, MUTAGENESIS OF SER-148; SER-229; SER-231; THR-244 AND SER-256.
[8]	"Two novel mutations in the aquaporin-2 and the vasopressin V2 receptor genes in patients with congenital nephrogenic diabetes insipidus." Oksche A., Moeller A., Dickson J., Rosendahl W., Rascher W., Bichet D.G., Rosenthal W. Hum. Genet. 98:587-589(1996) [PubMed: 8882880] [Abstract] Cited for: VARIANT ANDI CYS-202.
[9]	"Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response." Canfield M.C., Tamarappoo B.K., Moses A.M., Verkman A.S., Holtzman E.J. Hum. Mol. Genet. 6:1865-1871(1997) [PubMed: 9302264] [Abstract] Cited for: VARIANTS ANDI VAL-22 AND TRP-181.
[10]	"New mutations in the AQP2 gene in nephrogenic diabetes insipidus resulting in functional but misrouted water channels." Mulders S.M., Knoers N.V., Van Lieburg A.F., Monnens L.A., Leumann E., Wuhl E., Schober E., Rijss J.P.L., Van Os C.H., Deen P.M.T. J. Am. Soc. Nephrol. 8:242-248(1997) [PubMed: 9048343] [Abstract] Cited for: VARIANTS ANDI SER-68; MET-126 AND THR-147.
[11]	"Mutations in the vasopressin V2 receptor and aquaporin-2 genes in 12 families with congenital nephrogenic diabetes insipidus." Vargas-Poussou R., Forestier L., Dautzenberg M.D., Niaudet P., Dechaux M., Antignac C. J. Am. Soc. Nephrol. 8:1855-1862(1997) [PubMed: 9402087] [Abstract] Cited for: VARIANTS ANDI MET-168 AND PRO-216.
[12]	"Aquaporin-2, a vasopressin-sensitive water channel, and nephrogenic diabetes insipidus." Kuwahara M. Intern. Med. 37:215-217(1998) [PubMed: 9550615] [Abstract] Cited for: VARIANTS ANDI MET-125; ARG-175; THR-190 AND LEU-262.
[13]	"An aquaporin-2 water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the Golgi complex." Mulders S.M., Bichet D.G., Rijss J.P.L., Kamsteeg E.-J., Arthus M.-F., Lonergan M., Fujiwara M., Morgan K., Leijendekker R., van der Sluijs P., van Os C.H., Deen P.M.T. J. Clin. Invest. 102:57-66(1998) [PubMed: 9649557] [Abstract] Cited for: VARIANT ANDI LYS-258.
[14]	"Novel mutations in aquaporin-2 gene in female siblings with nephrogenic diabetes insipidus: evidence of disrupted water channel function." Goji K., Kuwahara M., Gu Y., Matsuo M., Marumo F., Sasaki S. J. Clin. Endocrinol. Metab. 83:3205-3209(1998) [PubMed: 9745427] [Abstract] Cited for: VARIANTS ANDI MET-125 AND ARG-175.
[15]	"Cell-biologic and functional analyses of five new Aquaporin-2 missense mutations that cause recessive nephrogenic diabetes insipidus." Marr N., Bichet D.G., Hoefs S., Savelkoul P.J.M., Konings I.B., De Mattia F., Graat M.P., Arthus M.-F., Lonergan M., Fujiwara T.M., Knoers N.V., Landau D., Balfe W.J., Oksche A., Rosenthal W., Muller D., Van Os C.H., Deen P.M. J. Am. Soc. Nephrol. 13:2267-2277(2002) [PubMed: 12191971] [Abstract] Cited for: VARIANTS ANDI PRO-28; VAL-47; MET-71; MET-125; ARG-175 AND ALA-185, VARIANT ILE-194.
[16]	"Two novel aquaporin-2 mutations responsible for congenital nephrogenic diabetes insipidus in Chinese families." Lin S.H., Bichet D.G., Sasaki S., Kuwahara M., Arthus M.-F., Lonergan M., Lin Y.-F. J. Clin. Endocrinol. Metab. 87:2694-2700(2002) [PubMed: 12050236] [Abstract] Cited for: VARIANTS ANDI PRO-57 AND VAL-100.
[17]	"A novel mechanism in recessive nephrogenic diabetes insipidus: wild-type aquaporin-2 rescues the apical membrane expression of intracellularly retained AQP2-P262L." de Mattia F., Savelkoul P.J.M., Bichet D.G., Kamsteeg E.-J., Konings I.B.M., Marr N., Arthus M.-F., Lonergan M., van Os C.H., van der Sluijs P., Robertson G., Deen P.M.T. Hum. Mol. Genet. 13:3045-3056(2004) [PubMed: 15509592] [Abstract] Cited for: VARIANTS ANDI CYS-187; THR-190 AND LEU-262, CHARACTERIZATION OF VARIANTS ANDI CYS-187; THR-190 AND LEU-262.
+	Additional computationally mapped references.

Web resources

Nephrogenic and neurogenic Diabetes Insipidus

AQP2 pages

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	Z29491 Genomic DNA. Translation: CAA82627.1. D31846 Genomic DNA. Translation: BAA06632.1. S73196 mRNA. Translation: AAB31999.1. S73197 mRNA. Translation: AAB31998.1. AF147093, AF147092 Genomic DNA. Translation: AAD38692.1. BC042496 mRNA. Translation: AAH42496.1.
IPI	IPI00012818.
PIR	A53442. I64818.
RefSeq	NP_000477.1.
UniGene	Hs.130730
3D structure databases
ModBase	Search...
Protein-protein interaction databases
STRING	P41181.
Protein family/group databases
TCDB	1.A.8.8.8. major intrinsic protein (MIP) family.
PTM databases
PhosphoSite	P41181.
Proteomic databases
PRIDE	P41181.
Genome annotation databases
Ensembl	ENST00000199280; ENSP00000199280; ENSG00000167580; Homo sapiens. [Genome view]
GeneID	359.
KEGG	hsa:359.
UCSC	uc001rvn.1. human.
Organism-specific databases
CTD	359.
GeneCards	GC12P048630.
H-InvDB	HIX0010617.
HGNC	HGNC:634. AQP2.
HPA	CAB009866.
MIM	107777. gene. 125800. phenotype.
Orphanet	223. Diabetes insipidus, nephrogenic.
PharmGKB	PA24920.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P41181.
HOVERGEN	P41181.
OMA	YVLFPPA
OrthoDB	EOG9P2SMS
Gene expression databases
ArrayExpress	P41181.
Bgee	P41181.
CleanEx	HS_AQP2.
Genevestigator	P41181.
GermOnline	ENSG00000167580. Homo sapiens.
Family and domain databases
InterPro	IPR012269. Aquaporin. IPR000425. MIP. [Graphical view]
Gene3D	G3DSA:1.20.1080.10. MIP. 1 hit.
PANTHER	PTHR19139. MIP. 1 hit.
Pfam	PF00230. MIP. 1 hit. [Graphical view]
PRINTS	PR00783. MINTRINSICP.
TIGRFAMs	TIGR00861. MIP. 1 hit.
PROSITE	PS00221. MIP. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	1501.
SOURCE	Search...

Entry information

Entry name

AQP2_HUMAN

Accession

Primary (citable) accession number: P41181
Secondary accession number(s): Q9UD68

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	February 1, 1995
Last modified:	November 24, 2009
This is version 97 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.