ID AQP2_HUMAN Reviewed; 271 AA. AC P41181; Q9UD68; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1995, sequence version 1. DT 24-JAN-2024, entry version 208. DE RecName: Full=Aquaporin-2; DE Short=AQP-2; DE AltName: Full=ADH water channel; DE AltName: Full=Aquaporin-CD {ECO:0000303|PubMed:7522228}; DE Short=AQP-CD; DE AltName: Full=Collecting duct water channel protein; DE AltName: Full=WCH-CD; DE AltName: Full=Water channel protein for renal collecting duct; GN Name=AQP2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, SUBCELLULAR LOCATION, VARIANTS RP NDI2 CYS-187 AND PRO-216, AND CHARACTERIZATION OF VARIANTS NDI2 CYS-187 AND RP PRO-216. RX PubMed=8140421; DOI=10.1126/science.8140421; RA Deen P.M.T., Verdijk M.A.J., Knoers V.V.A.M., Wieringa B., Monnens L.A.H., RA van Os C.H., van Oost B.A.; RT "Requirement of human renal water channel aquaporin-2 for vasopressin- RT dependent concentration of urine."; RL Science 264:92-94(1994). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=7522228; DOI=10.1016/s0021-9258(17)31537-5; RA Uchida S., Sasaki S., Fushimi K., Marumo F.; RT "Isolation of human aquaporin-CD gene."; RL J. Biol. Chem. 269:23451-23455(1994). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, VARIANTS NDI2 RP ARG-64; CYS-187 AND PRO-216, AND CHARACTERIZATION OF VARIANT NDI2 ARG-64. RX PubMed=7524315; RA van Lieburg A.F., Verdijk M.A.J., Knoers V.V.A.M., van Essen A.J., RA Proesmans W., Mallmann R., Monnens L.A.H., van Oost B.A., van Os C.H., RA Deen P.M.T.; RT "Patients with autosomal nephrogenic diabetes insipidus homozygous for RT mutations in the aquaporin 2 water-channel gene."; RL Am. J. Hum. Genet. 55:648-652(1994). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE RP SPECIFICITY, AND GLYCOSYLATION. RC TISSUE=Kidney; RX PubMed=7510718; DOI=10.1172/jci117079; RA Sasaki S., Fushimi K., Saito H., Saito F., Uchida S., Ishibashi K., RA Kuwahara M., Ikeuchi T., Inui K., Nakajima K.; RT "Cloning, characterization, and chromosomal mapping of human aquaporin of RT collecting duct."; RL J. Clin. Invest. 93:1250-1256(1994). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Kidney; RX PubMed=11929850; DOI=10.1093/hmg/11.7.779; RA Marr N., Bichet D.G., Lonergan M., Arthus M.-F., Jeck N., Seyberth H.W., RA Rosenthal W., van Os C.H., Oksche A., Deen P.M.T.; RT "Heteroligomerization of an aquaporin-2 mutant with wild-type aquaporin-2 RT and their misrouting to late endosomes/lysosomes explains dominant RT nephrogenic diabetes insipidus."; RL Hum. Mol. Genet. 11:779-789(2002). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Colon; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-256, AND MUTAGENESIS OF RP SER-148; SER-229; SER-231; THR-244 AND SER-256. RX PubMed=12194985; DOI=10.1074/jbc.m207525200; RA van Balkom B.W.M., Savelkoul P.J.M., Markovich D., Hofman E., Nielsen S., RA van der Sluijs P., Deen P.M.T.; RT "The role of putative phosphorylation sites in the targeting and shuttling RT of the aquaporin-2 water channel."; RL J. Biol. Chem. 277:41473-41479(2002). RN [8] RP INTERACTION WITH MIAC. RX PubMed=32176498; DOI=10.1021/jacs.0c00706; RA Li M., Li X., Zhang Y., Wu H., Zhou H., Ding X., Zhang X., Jin X., Wang Y., RA Yin X., Li C., Yang P., Xu H.; RT "Micropeptide MIAC Inhibits HNSCC Progression by Interacting with Aquaporin RT 2."; RL J. Am. Chem. Soc. 142:6708-6716(2020). RN [9] {ECO:0000305} RP INTERACTION WITH MIAC, AND MUTAGENESIS OF GLY-78; CYS-79; LEU-217; TYR-221 RP AND GLU-232. RX PubMed=36117171; DOI=10.1186/s12943-022-01654-1; RA Li M., Liu G., Jin X., Guo H., Setrerrahmane S., Xu X., Li T., Lin Y., RA Xu H.; RT "Micropeptide MIAC inhibits the tumor progression by interacting with AQP2 RT and inhibiting EREG/EGFR signaling in renal cell carcinoma."; RL Mol. Cancer 21:181-181(2022). RN [10] {ECO:0007744|PDB:4NEF} RP X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF 3-241, SUBUNIT, SUBCELLULAR RP LOCATION, TOPOLOGY, AND DOMAIN. RX PubMed=24733887; DOI=10.1073/pnas.1321406111; RA Frick A., Eriksson U.K., de Mattia F., Oberg F., Hedfalk K., Neutze R., RA de Grip W.J., Deen P.M., Tornroth-Horsefield S.; RT "X-ray structure of human aquaporin 2 and its implications for nephrogenic RT diabetes insipidus and trafficking."; RL Proc. Natl. Acad. Sci. U.S.A. 111:6305-6310(2014). RN [11] RP VARIANT NDI2 CYS-202. RX PubMed=8882880; DOI=10.1007/s004390050264; RA Oksche A., Moeller A., Dickson J., Rosendahl W., Rascher W., Bichet D.G., RA Rosenthal W.; RT "Two novel mutations in the aquaporin-2 and the vasopressin V2 receptor RT genes in patients with congenital nephrogenic diabetes insipidus."; RL Hum. Genet. 98:587-589(1996). RN [12] RP VARIANTS NDI2 VAL-22 AND TRP-181. RX PubMed=9302264; DOI=10.1093/hmg/6.11.1865; RA Canfield M.C., Tamarappoo B.K., Moses A.M., Verkman A.S., Holtzman E.J.; RT "Identification and characterization of aquaporin-2 water channel mutations RT causing nephrogenic diabetes insipidus with partial vasopressin response."; RL Hum. Mol. Genet. 6:1865-1871(1997). RN [13] RP VARIANTS NDI2 SER-68; MET-126 AND THR-147. RX PubMed=9048343; DOI=10.1681/asn.v82242; RA Mulders S.M., Knoers N.V., Van Lieburg A.F., Monnens L.A., Leumann E., RA Wuhl E., Schober E., Rijss J.P.L., Van Os C.H., Deen P.M.T.; RT "New mutations in the AQP2 gene in nephrogenic diabetes insipidus resulting RT in functional but misrouted water channels."; RL J. Am. Soc. Nephrol. 8:242-248(1997). RN [14] RP VARIANTS NDI2 MET-168 AND PRO-216. RX PubMed=9402087; DOI=10.1681/asn.v8121855; RA Vargas-Poussou R., Forestier L., Dautzenberg M.D., Niaudet P., Dechaux M., RA Antignac C.; RT "Mutations in the vasopressin V2 receptor and aquaporin-2 genes in 12 RT families with congenital nephrogenic diabetes insipidus."; RL J. Am. Soc. Nephrol. 8:1855-1862(1997). RN [15] RP VARIANTS NDI2 MET-125; ARG-175; THR-190 AND LEU-262. RX PubMed=9550615; DOI=10.2169/internalmedicine.37.215; RA Kuwahara M.; RT "Aquaporin-2, a vasopressin-sensitive water channel, and nephrogenic RT diabetes insipidus."; RL Intern. Med. 37:215-217(1998). RN [16] RP VARIANT NDI2 LYS-258. RX PubMed=9649557; DOI=10.1172/jci2605; RA Mulders S.M., Bichet D.G., Rijss J.P.L., Kamsteeg E.-J., Arthus M.-F., RA Lonergan M., Fujiwara M., Morgan K., Leijendekker R., van der Sluijs P., RA van Os C.H., Deen P.M.T.; RT "An aquaporin-2 water channel mutant which causes autosomal dominant RT nephrogenic diabetes insipidus is retained in the Golgi complex."; RL J. Clin. Invest. 102:57-66(1998). RN [17] RP VARIANTS NDI2 MET-125 AND ARG-175. RX PubMed=9745427; DOI=10.1210/jcem.83.9.5074; RA Goji K., Kuwahara M., Gu Y., Matsuo M., Marumo F., Sasaki S.; RT "Novel mutations in aquaporin-2 gene in female siblings with nephrogenic RT diabetes insipidus: evidence of disrupted water channel function."; RL J. Clin. Endocrinol. Metab. 83:3205-3209(1998). RN [18] RP VARIANTS NDI2 PRO-28; VAL-47; MET-71; MET-125; ARG-175 AND ALA-185, AND RP VARIANT ILE-194. RX PubMed=12191971; DOI=10.1097/01.asn.0000027355.41663.14; RA Marr N., Bichet D.G., Hoefs S., Savelkoul P.J.M., Konings I.B., RA De Mattia F., Graat M.P., Arthus M.-F., Lonergan M., Fujiwara T.M., RA Knoers N.V., Landau D., Balfe W.J., Oksche A., Rosenthal W., Muller D., RA Van Os C.H., Deen P.M.; RT "Cell-biologic and functional analyses of five new Aquaporin-2 missense RT mutations that cause recessive nephrogenic diabetes insipidus."; RL J. Am. Soc. Nephrol. 13:2267-2277(2002). RN [19] RP VARIANTS NDI2 PRO-57 AND VAL-100. RX PubMed=12050236; DOI=10.1210/jcem.87.6.8617; RA Lin S.H., Bichet D.G., Sasaki S., Kuwahara M., Arthus M.-F., Lonergan M., RA Lin Y.-F.; RT "Two novel aquaporin-2 mutations responsible for congenital nephrogenic RT diabetes insipidus in Chinese families."; RL J. Clin. Endocrinol. Metab. 87:2694-2700(2002). RN [20] RP VARIANTS NDI2 CYS-187; THR-190 AND LEU-262, CHARACTERIZATION OF VARIANTS RP NDI2 CYS-187; THR-190 AND LEU-262, FUNCTION, SUBCELLULAR LOCATION, AND RP MUTAGENESIS OF PRO-262. RX PubMed=15509592; DOI=10.1093/hmg/ddh339; RA de Mattia F., Savelkoul P.J.M., Bichet D.G., Kamsteeg E.-J., RA Konings I.B.M., Marr N., Arthus M.-F., Lonergan M., van Os C.H., RA van der Sluijs P., Robertson G., Deen P.M.T.; RT "A novel mechanism in recessive nephrogenic diabetes insipidus: wild-type RT aquaporin-2 rescues the apical membrane expression of intracellularly RT retained AQP2-P262L."; RL Hum. Mol. Genet. 13:3045-3056(2004). RN [21] RP VARIANT NDI2 LEU-254, AND CHARACTERIZATION OF VARIANT NDI2 LEU-254. RX PubMed=16120822; DOI=10.1681/asn.2005010104; RA de Mattia F., Savelkoul P.J.M., Kamsteeg E.-J., Konings I.B.M., RA van der Sluijs P., Mallmann R., Oksche A., Deen P.M.T.; RT "Lack of arginine vasopressin-induced phosphorylation of aquaporin-2 mutant RT AQP2-R254L explains dominant nephrogenic diabetes insipidus."; RL J. Am. Soc. Nephrol. 16:2872-2880(2005). RN [22] RP VARIANTS NDI2 ASP-70 AND HIS-187. RX PubMed=16361827; DOI=10.3346/jkms.2005.20.6.1076; RA Cheong H.I., Cho S.J., Zheng S.H., Cho H.Y., Ha I.S., Choi Y.; RT "Two novel mutations in the aquaporin 2 gene in a girl with congenital RT nephrogenic diabetes insipidus."; RL J. Korean Med. Sci. 20:1076-1078(2005). RN [23] RP VARIANTS NDI2 ARG-100 AND SER-180. RX PubMed=16845277; DOI=10.1097/01.gim.0000223554.46981.7a; RA Carroll P., Al-Mojalli H., Al-Abbad A., Al-Hassoun I., Al-Hamed M., RA Al-Amr R., Butt A.I., Meyer B.F.; RT "Novel mutations underlying nephrogenic diabetes insipidus in Arab RT families."; RL Genet. Med. 8:443-447(2006). RN [24] RP INVOLVEMENT IN NDI2, VARIANT NDI2 GLN-254, AND CHARACTERIZATION OF VARIANT RP NDI2 GLN-254. RX PubMed=19585583; DOI=10.1002/humu.21082; RA Savelkoul P.J.M., De Mattia F., Li Y., Kamsteeg E.-J., Konings I.B.M., RA van der Sluijs P., Deen P.M.T.; RT "p.R254Q mutation in the aquaporin-2 water channel causing dominant RT nephrogenic diabetes insipidus is due to a lack of arginine vasopressin- RT induced phosphorylation."; RL Hum. Mutat. 30:E891-E903(2009). RN [25] RP MISSORTING MOTIF OF VARIANT NDI2 LYS-258. RX PubMed=19701945; DOI=10.1002/humu.21068; RA Kamsteeg E.-J., Stoffels M., Tamma G., Konings I.B.M., Deen P.M.T.; RT "Repulsion between Lys258 and upstream arginines explains the missorting of RT the AQP2 mutant p.Glu258Lys in nephrogenic diabetes insipidus."; RL Hum. Mutat. 30:1387-1396(2009). RN [26] RP VARIANT NDI2 MET-108. RX PubMed=24944815; DOI=10.3892/br.2014.283; RA Park Y.J., Baik H.W., Cheong H.I., Kang J.H.; RT "Congenital nephrogenic diabetes insipidus with a novel mutation in the RT aquaporin 2 gene."; RL Biomed. Rep. 2:596-598(2014). CC -!- FUNCTION: Forms a water-specific channel that provides the plasma CC membranes of renal collecting duct with high permeability to water, CC thereby permitting water to move in the direction of an osmotic CC gradient (PubMed:8140421, PubMed:7524315, PubMed:7510718, CC PubMed:15509592). Plays an essential role in renal water homeostasis CC (PubMed:8140421, PubMed:7524315, PubMed:15509592). CC {ECO:0000269|PubMed:15509592, ECO:0000269|PubMed:7510718, CC ECO:0000269|PubMed:7524315, ECO:0000269|PubMed:8140421}. CC -!- SUBUNIT: Homotetramer (PubMed:24733887). Interacts with micropeptide CC MIAC; the interaction leads to a reduction of filamentous actin fibers CC and inhibition of the EREG/EGFR signaling pathway (PubMed:32176498, CC PubMed:36117171). {ECO:0000269|PubMed:24733887, CC ECO:0000269|PubMed:32176498, ECO:0000269|PubMed:36117171}. CC -!- INTERACTION: CC P41181; O14735: CDIPT; NbExp=3; IntAct=EBI-12701138, EBI-358858; CC P41181; O43889-2: CREB3; NbExp=3; IntAct=EBI-12701138, EBI-625022; CC P41181; Q96BA8: CREB3L1; NbExp=3; IntAct=EBI-12701138, EBI-6942903; CC P41181; P52803: EFNA5; NbExp=3; IntAct=EBI-12701138, EBI-1753674; CC P41181; Q9UKR5: ERG28; NbExp=3; IntAct=EBI-12701138, EBI-711490; CC P41181; Q9Y282: ERGIC3; NbExp=3; IntAct=EBI-12701138, EBI-781551; CC P41181; Q7Z2K6: ERMP1; NbExp=3; IntAct=EBI-12701138, EBI-10976398; CC P41181; Q5JX71: FAM209A; NbExp=3; IntAct=EBI-12701138, EBI-18304435; CC P41181; Q92520: FAM3C; NbExp=3; IntAct=EBI-12701138, EBI-2876774; CC P41181; Q8TED1: GPX8; NbExp=3; IntAct=EBI-12701138, EBI-11721746; CC P41181; P24593: IGFBP5; NbExp=3; IntAct=EBI-12701138, EBI-720480; CC P41181; Q9Y5U4: INSIG2; NbExp=3; IntAct=EBI-12701138, EBI-8503746; CC P41181; A8MZ59: LEUTX; NbExp=3; IntAct=EBI-12701138, EBI-17490413; CC P41181; Q8TAF8: LHFPL5; NbExp=3; IntAct=EBI-12701138, EBI-2820517; CC P41181; Q6IN84: MRM1; NbExp=3; IntAct=EBI-12701138, EBI-5454865; CC P41181; Q5J8X5: MS4A13; NbExp=3; IntAct=EBI-12701138, EBI-12070086; CC P41181; P15941-11: MUC1; NbExp=3; IntAct=EBI-12701138, EBI-17263240; CC P41181; Q8IXM6: NRM; NbExp=3; IntAct=EBI-12701138, EBI-10262547; CC P41181; Q6UX06: OLFM4; NbExp=3; IntAct=EBI-12701138, EBI-2804156; CC P41181; Q8NH19: OR10AG1; NbExp=3; IntAct=EBI-12701138, EBI-13339917; CC P41181; Q96RD7: PANX1; NbExp=3; IntAct=EBI-12701138, EBI-7037612; CC P41181; Q13113: PDZK1IP1; NbExp=3; IntAct=EBI-12701138, EBI-716063; CC P41181; Q01453: PMP22; NbExp=3; IntAct=EBI-12701138, EBI-2845982; CC P41181; P54315: PNLIPRP1; NbExp=3; IntAct=EBI-12701138, EBI-8652812; CC P41181; Q59EV6: PPGB; NbExp=3; IntAct=EBI-12701138, EBI-14210385; CC P41181; Q5QGT7: RTP2; NbExp=3; IntAct=EBI-12701138, EBI-10244780; CC P41181; Q9BXS9-3: SLC26A6; NbExp=3; IntAct=EBI-12701138, EBI-12814225; CC P41181; Q9BRI3: SLC30A2; NbExp=3; IntAct=EBI-12701138, EBI-8644112; CC P41181; Q9NVC3: SLC38A7; NbExp=3; IntAct=EBI-12701138, EBI-10314552; CC P41181; Q5SQN1: SNAP47; NbExp=3; IntAct=EBI-12701138, EBI-10244848; CC P41181; Q9BVC6: TMEM109; NbExp=3; IntAct=EBI-12701138, EBI-1057733; CC P41181; A2RU14: TMEM218; NbExp=3; IntAct=EBI-12701138, EBI-10173151; CC P41181; Q5W0B7: TMEM236; NbExp=3; IntAct=EBI-12701138, EBI-13378608; CC P41181; Q9H2L4: TMEM60; NbExp=3; IntAct=EBI-12701138, EBI-2852148; CC P41181; Q8N2M4: TMEM86A; NbExp=3; IntAct=EBI-12701138, EBI-12015604; CC P41181; Q5BJF2: TMEM97; NbExp=3; IntAct=EBI-12701138, EBI-12111910; CC P41181; A5PKU2: TUSC5; NbExp=3; IntAct=EBI-12701138, EBI-11988865; CC P41181; Q96EC8: YIPF6; NbExp=3; IntAct=EBI-12701138, EBI-751210; CC -!- SUBCELLULAR LOCATION: Apical cell membrane CC {ECO:0000269|PubMed:12194985, ECO:0000269|PubMed:15509592, CC ECO:0000269|PubMed:7510718}; Multi-pass membrane protein CC {ECO:0000269|PubMed:12194985, ECO:0000269|PubMed:24733887}. Basolateral CC cell membrane {ECO:0000250|UniProtKB:P34080}; Multi-pass membrane CC protein {ECO:0000269|PubMed:24733887}. Cell membrane CC {ECO:0000269|PubMed:15509592, ECO:0000269|PubMed:24733887, CC ECO:0000269|PubMed:7524315, ECO:0000269|PubMed:8140421}; Multi-pass CC membrane protein {ECO:0000269|PubMed:24733887}. Cytoplasmic vesicle CC membrane {ECO:0000269|PubMed:12194985, ECO:0000269|PubMed:15509592}; CC Multi-pass membrane protein {ECO:0000269|PubMed:12194985, CC ECO:0000269|PubMed:24733887}. Golgi apparatus, trans-Golgi network CC membrane {ECO:0000269|PubMed:12194985}; Multi-pass membrane protein CC {ECO:0000269|PubMed:12194985, ECO:0000269|PubMed:24733887}. CC Note=Shuttles from vesicles to the apical membrane (PubMed:15509592). CC Vasopressin-regulated phosphorylation is required for translocation to CC the apical cell membrane (PubMed:15509592). PLEKHA8/FAPP2 is required CC to transport AQP2 from the TGN to sites where AQP2 is phosphorylated CC (By similarity). {ECO:0000250|UniProtKB:P34080, CC ECO:0000269|PubMed:15509592}. CC -!- TISSUE SPECIFICITY: Expressed in collecting tubules in kidney medulla CC (at protein level) (PubMed:7510718). Detected in kidney CC (PubMed:7510718). {ECO:0000269|PubMed:7510718}. CC -!- DOMAIN: Aquaporins contain two tandem repeats each containing three CC membrane-spanning domains and a pore-forming loop with the signature CC motif Asn-Pro-Ala (NPA). {ECO:0000269|PubMed:24733887}. CC -!- PTM: Ser-256 phosphorylation is necessary and sufficient for expression CC at the apical membrane. Endocytosis is not phosphorylation-dependent. CC {ECO:0000269|PubMed:12194985}. CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:7510718}. CC -!- DISEASE: Diabetes insipidus, nephrogenic, 2, autosomal (NDI2) CC [MIM:125800]: A disorder caused by the inability of the renal CC collecting ducts to absorb water in response to arginine vasopressin. CC Characterized by excessive water drinking (polydipsia), excessive urine CC excretion (polyuria), persistent hypotonic urine, and hypokalemia. CC Inheritance can be autosomal dominant or recessive. CC {ECO:0000269|PubMed:12050236, ECO:0000269|PubMed:12191971, CC ECO:0000269|PubMed:15509592, ECO:0000269|PubMed:16120822, CC ECO:0000269|PubMed:16361827, ECO:0000269|PubMed:16845277, CC ECO:0000269|PubMed:19585583, ECO:0000269|PubMed:19701945, CC ECO:0000269|PubMed:24944815, ECO:0000269|PubMed:7524315, CC ECO:0000269|PubMed:8140421, ECO:0000269|PubMed:8882880, CC ECO:0000269|PubMed:9048343, ECO:0000269|PubMed:9302264, CC ECO:0000269|PubMed:9402087, ECO:0000269|PubMed:9550615, CC ECO:0000269|PubMed:9649557, ECO:0000269|PubMed:9745427}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the MIP/aquaporin (TC 1.A.8) family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Z29491; CAA82627.1; -; Genomic_DNA. DR EMBL; D31846; BAA06632.1; -; Genomic_DNA. DR EMBL; S73196; AAB31999.1; -; mRNA. DR EMBL; S73197; AAB31998.1; -; mRNA. DR EMBL; AF147093; AAD38692.1; -; Genomic_DNA. DR EMBL; AF147092; AAD38692.1; JOINED; Genomic_DNA. DR EMBL; BC042496; AAH42496.1; -; mRNA. DR CCDS; CCDS8792.1; -. DR PIR; A53442; A53442. DR PIR; I64818; I64818. DR RefSeq; NP_000477.1; NM_000486.5. DR PDB; 4NEF; X-ray; 2.75 A; A/B/C/D=3-241. DR PDB; 4OJ2; X-ray; 3.05 A; X=1-271. DR PDB; 6QF5; X-ray; 3.70 A; A/B/C/D=3-242. DR PDB; 8GCL; EM; 2.90 A; A=1-271. DR PDB; 8GHJ; X-ray; 3.90 A; A/B/C/D=3-241. DR PDB; 8OEE; X-ray; 3.15 A; A/B/C/D=3-241. DR PDBsum; 4NEF; -. DR PDBsum; 4OJ2; -. DR PDBsum; 6QF5; -. DR PDBsum; 8GCL; -. DR PDBsum; 8GHJ; -. DR PDBsum; 8OEE; -. DR AlphaFoldDB; P41181; -. DR EMDB; EMD-29934; -. DR SMR; P41181; -. DR BioGRID; 106855; 67. DR IntAct; P41181; 38. DR STRING; 9606.ENSP00000199280; -. DR ChEMBL; CHEMBL4523224; -. DR TCDB; 1.A.8.8.8; the major intrinsic protein (mip) family. DR GlyCosmos; P41181; 1 site, No reported glycans. DR GlyGen; P41181; 1 site. DR iPTMnet; P41181; -. DR PhosphoSitePlus; P41181; -. DR BioMuta; AQP2; -. DR DMDM; 728874; -. DR jPOST; P41181; -. DR MassIVE; P41181; -. DR PaxDb; 9606-ENSP00000199280; -. DR PeptideAtlas; P41181; -. DR ProteomicsDB; 55412; -. DR Antibodypedia; 4081; 735 antibodies from 39 providers. DR DNASU; 359; -. DR Ensembl; ENST00000199280.4; ENSP00000199280.3; ENSG00000167580.8. DR GeneID; 359; -. DR KEGG; hsa:359; -. DR MANE-Select; ENST00000199280.4; ENSP00000199280.3; NM_000486.6; NP_000477.1. DR UCSC; uc001rvn.4; human. DR AGR; HGNC:634; -. DR CTD; 359; -. DR DisGeNET; 359; -. DR GeneCards; AQP2; -. DR GeneReviews; AQP2; -. DR HGNC; HGNC:634; AQP2. DR HPA; ENSG00000167580; Group enriched (kidney, seminal vesicle). DR MalaCards; AQP2; -. DR MIM; 107777; gene. DR MIM; 125800; phenotype. DR neXtProt; NX_P41181; -. DR OpenTargets; ENSG00000167580; -. DR Orphanet; 223; Nephrogenic diabetes insipidus. DR PharmGKB; PA24920; -. DR VEuPathDB; HostDB:ENSG00000167580; -. DR eggNOG; KOG0223; Eukaryota. DR GeneTree; ENSGT00940000160612; -. DR InParanoid; P41181; -. DR OMA; LEPDVDW; -. DR OrthoDB; 3236018at2759; -. DR PhylomeDB; P41181; -. DR TreeFam; TF312940; -. DR PathwayCommons; P41181; -. DR Reactome; R-HSA-432040; Vasopressin regulates renal water homeostasis via Aquaporins. DR Reactome; R-HSA-432047; Passive transport by Aquaporins. DR SignaLink; P41181; -. DR SIGNOR; P41181; -. DR BioGRID-ORCS; 359; 24 hits in 1152 CRISPR screens. DR GeneWiki; Aquaporin_2; -. DR GenomeRNAi; 359; -. DR Pharos; P41181; Tbio. DR PRO; PR:P41181; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; P41181; Protein. DR Bgee; ENSG00000167580; Expressed in renal medulla and 78 other cell types or tissues. DR ExpressionAtlas; P41181; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB. DR GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell. DR GO; GO:0098576; C:lumenal side of membrane; IEA:Ensembl. DR GO; GO:0016020; C:membrane; IDA:MGI. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0055037; C:recycling endosome; IEA:Ensembl. DR GO; GO:0030658; C:transport vesicle membrane; TAS:Reactome. DR GO; GO:0015168; F:glycerol transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0015250; F:water channel activity; IMP:UniProtKB. DR GO; GO:0005372; F:water transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0007015; P:actin filament organization; IMP:UniProtKB. DR GO; GO:0071280; P:cellular response to copper ion; IDA:UniProtKB. DR GO; GO:0071288; P:cellular response to mercury ion; IDA:UniProtKB. DR GO; GO:0042631; P:cellular response to water deprivation; IEA:Ensembl. DR GO; GO:0015793; P:glycerol transmembrane transport; IDA:UniProtKB. DR GO; GO:0072205; P:metanephric collecting duct development; IEA:Ensembl. DR GO; GO:0051289; P:protein homotetramerization; IDA:UniProtKB. DR GO; GO:0003091; P:renal water homeostasis; IMP:UniProtKB. DR GO; GO:0003097; P:renal water transport; IEA:Ensembl. DR GO; GO:0006833; P:water transport; IDA:UniProtKB. DR CDD; cd00333; MIP; 1. DR Gene3D; 1.20.1080.10; Glycerol uptake facilitator protein; 1. DR InterPro; IPR023271; Aquaporin-like. DR InterPro; IPR034294; Aquaporin_transptr. DR InterPro; IPR000425; MIP. DR InterPro; IPR022357; MIP_CS. DR NCBIfam; TIGR00861; MIP; 1. DR PANTHER; PTHR19139; AQUAPORIN TRANSPORTER; 1. DR PANTHER; PTHR19139:SF45; AQUAPORIN-2; 1. DR Pfam; PF00230; MIP; 1. DR PRINTS; PR02014; AQUAPORIN2. DR PRINTS; PR00783; MINTRINSICP. DR SUPFAM; SSF81338; Aquaporin-like; 1. DR PROSITE; PS00221; MIP; 1. DR Genevisible; P41181; HS. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Cytoplasmic vesicle; Diabetes insipidus; KW Disease variant; Glycoprotein; Golgi apparatus; Membrane; Phosphoprotein; KW Reference proteome; Repeat; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..271 FT /note="Aquaporin-2" FT /id="PRO_0000063934" FT TOPO_DOM 1..11 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:24733887" FT TRANSMEM 12..32 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:24733887" FT TOPO_DOM 33..40 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:24733887" FT TRANSMEM 41..59 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:24733887" FT TOPO_DOM 60..64 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:24733887" FT INTRAMEM 65..74 FT /note="Discontinuously helical" FT /evidence="ECO:0000269|PubMed:24733887" FT TOPO_DOM 75..85 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:24733887" FT TRANSMEM 86..107 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:24733887" FT TOPO_DOM 108..127 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:24733887" FT TRANSMEM 128..148 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:24733887" FT TOPO_DOM 149..156 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:24733887" FT TRANSMEM 157..176 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:24733887" FT TOPO_DOM 177..180 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:24733887" FT INTRAMEM 181..193 FT /note="Discontinuously helical" FT /evidence="ECO:0000269|PubMed:24733887" FT TOPO_DOM 194..201 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:24733887" FT TRANSMEM 202..222 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:24733887" FT TOPO_DOM 223..271 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT REGION 248..271 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 68..70 FT /note="NPA 1" FT /evidence="ECO:0000305|PubMed:24733887" FT MOTIF 184..186 FT /note="NPA 2" FT /evidence="ECO:0000305|PubMed:24733887" FT MOD_RES 256 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:12194985" FT CARBOHYD 123 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VARIANT 22 FT /note="L -> V (in NDI2; dbSNP:rs104894336)" FT /evidence="ECO:0000269|PubMed:9302264" FT /id="VAR_015239" FT VARIANT 28 FT /note="L -> P (in NDI2)" FT /evidence="ECO:0000269|PubMed:12191971" FT /id="VAR_015240" FT VARIANT 47 FT /note="A -> V (in NDI2; dbSNP:rs995684800)" FT /evidence="ECO:0000269|PubMed:12191971" FT /id="VAR_015241" FT VARIANT 57 FT /note="Q -> P (in NDI2; dbSNP:rs28931580)" FT /evidence="ECO:0000269|PubMed:12050236" FT /id="VAR_015256" FT VARIANT 64 FT /note="G -> R (in NDI2; loss of water channel activity; FT dbSNP:rs104894326)" FT /evidence="ECO:0000269|PubMed:7524315" FT /id="VAR_004401" FT VARIANT 68 FT /note="N -> S (in NDI2; dbSNP:rs104894331)" FT /evidence="ECO:0000269|PubMed:9048343" FT /id="VAR_015242" FT VARIANT 70 FT /note="A -> D (in NDI2)" FT /evidence="ECO:0000269|PubMed:16361827" FT /id="VAR_062585" FT VARIANT 71 FT /note="V -> M (in NDI2; dbSNP:rs149659001)" FT /evidence="ECO:0000269|PubMed:12191971" FT /id="VAR_015243" FT VARIANT 100 FT /note="G -> R (in NDI2; dbSNP:rs1303076207)" FT /evidence="ECO:0000269|PubMed:16845277" FT /id="VAR_062586" FT VARIANT 100 FT /note="G -> V (in NDI2; dbSNP:rs104894338)" FT /evidence="ECO:0000269|PubMed:12050236" FT /id="VAR_015257" FT VARIANT 108 FT /note="T -> M (in NDI2; dbSNP:rs1468828294)" FT /evidence="ECO:0000269|PubMed:24944815" FT /id="VAR_071370" FT VARIANT 121 FT /note="L -> F (in dbSNP:rs11169226)" FT /id="VAR_037577" FT VARIANT 125 FT /note="T -> M (in NDI2; dbSNP:rs104894333)" FT /evidence="ECO:0000269|PubMed:12191971, FT ECO:0000269|PubMed:9550615, ECO:0000269|PubMed:9745427" FT /id="VAR_015244" FT VARIANT 126 FT /note="T -> M (in NDI2; dbSNP:rs104894330)" FT /evidence="ECO:0000269|PubMed:9048343" FT /id="VAR_015245" FT VARIANT 147 FT /note="A -> T (in NDI2; dbSNP:rs104894334)" FT /evidence="ECO:0000269|PubMed:9048343" FT /id="VAR_015246" FT VARIANT 168 FT /note="V -> M (in NDI2; dbSNP:rs755694590)" FT /evidence="ECO:0000269|PubMed:9402087" FT /id="VAR_015247" FT VARIANT 175 FT /note="G -> R (in NDI2; dbSNP:rs104894335)" FT /evidence="ECO:0000269|PubMed:12191971, FT ECO:0000269|PubMed:9550615, ECO:0000269|PubMed:9745427" FT /id="VAR_015248" FT VARIANT 180 FT /note="G -> S (in NDI2; dbSNP:rs147039983)" FT /evidence="ECO:0000269|PubMed:16845277" FT /id="VAR_062587" FT VARIANT 181 FT /note="C -> W (in NDI2; dbSNP:rs104894337)" FT /evidence="ECO:0000269|PubMed:9302264" FT /id="VAR_015249" FT VARIANT 185 FT /note="P -> A (in NDI2; dbSNP:rs761713751)" FT /evidence="ECO:0000269|PubMed:12191971" FT /id="VAR_015250" FT VARIANT 187 FT /note="R -> C (in NDI2; loss of water channel activity; FT mutant protein does not fold properly; dbSNP:rs104894328)" FT /evidence="ECO:0000269|PubMed:15509592, FT ECO:0000269|PubMed:7524315, ECO:0000269|PubMed:8140421" FT /id="VAR_004402" FT VARIANT 187 FT /note="R -> H (in NDI2; dbSNP:rs193922495)" FT /evidence="ECO:0000269|PubMed:16361827" FT /id="VAR_062588" FT VARIANT 190 FT /note="A -> T (in NDI2; mutant protein does not fold FT properly and is not functional; dbSNP:rs104894341)" FT /evidence="ECO:0000269|PubMed:15509592, FT ECO:0000269|PubMed:9550615" FT /id="VAR_015251" FT VARIANT 194 FT /note="V -> I (in dbSNP:rs772051028)" FT /evidence="ECO:0000269|PubMed:12191971" FT /id="VAR_015252" FT VARIANT 202 FT /note="W -> C (in NDI2)" FT /evidence="ECO:0000269|PubMed:8882880" FT /id="VAR_015253" FT VARIANT 216 FT /note="S -> P (in NDI2; loss of water channel activity; FT dbSNP:rs104894329)" FT /evidence="ECO:0000269|PubMed:7524315, FT ECO:0000269|PubMed:8140421, ECO:0000269|PubMed:9402087" FT /id="VAR_004403" FT VARIANT 254 FT /note="R -> L (in NDI2; results in the loss of arginine FT vasopressin-mediated phosphorylation at S-256)" FT /evidence="ECO:0000269|PubMed:16120822" FT /id="VAR_062589" FT VARIANT 254 FT /note="R -> Q (in NDI2; exerts a dominant-negative effect FT on wild-type-AQP2 in that it interferes with its FT trafficking to the apical membrane; is a loss of function FT instead of a gain of function mutation on dominant FT nephrogenic diabetes insipidus)" FT /evidence="ECO:0000269|PubMed:19585583" FT /id="VAR_062590" FT VARIANT 258 FT /note="E -> K (in NDI2; retained in the Golgi compartment; FT dbSNP:rs104894332)" FT /evidence="ECO:0000269|PubMed:19701945, FT ECO:0000269|PubMed:9649557" FT /id="VAR_015254" FT VARIANT 262 FT /note="P -> L (in NDI2; mutant protein folds properly and FT is functional but is retained in intracellular vesicles; FT able to assemble into tetramers with wild-type AQP2 that FT properly localize to the apical membrane; FT dbSNP:rs104894339)" FT /evidence="ECO:0000269|PubMed:15509592, FT ECO:0000269|PubMed:9550615" FT /id="VAR_015255" FT MUTAGEN 78 FT /note="G->A: Does not affect interaction with MIAC; when FT associated with A-79." FT /evidence="ECO:0000269|PubMed:36117171" FT MUTAGEN 79 FT /note="C->A: Does not affect interaction with MIAC; when FT associated with A-78." FT /evidence="ECO:0000269|PubMed:36117171" FT MUTAGEN 148 FT /note="S->A: No effect on sorting from the ER to the FT vesicles, redistribution to apical membrane, or FT endocytosis." FT /evidence="ECO:0000269|PubMed:12194985" FT MUTAGEN 148 FT /note="S->D: Retained in the endoplasmic reticulum." FT /evidence="ECO:0000269|PubMed:12194985" FT MUTAGEN 217 FT /note="L->A: Abolishes interaction with MIAC; when FT associated with A-221." FT /evidence="ECO:0000269|PubMed:36117171" FT MUTAGEN 221 FT /note="Y->A: Abolishes interaction with MIAC; when FT associated with A-217." FT /evidence="ECO:0000269|PubMed:36117171" FT MUTAGEN 229 FT /note="S->A: No effect on sorting from the ER to the FT vesicles, redistribution to apical membrane, or FT endocytosis." FT /evidence="ECO:0000269|PubMed:12194985" FT MUTAGEN 229 FT /note="S->D: No effect on sorting from the ER to the FT vesicles, redistribution to apical membrane, or FT endocytosis." FT /evidence="ECO:0000269|PubMed:12194985" FT MUTAGEN 231 FT /note="S->A: No effect on sorting from the ER to the FT vesicles, redistribution to apical membrane, or FT endocytosis." FT /evidence="ECO:0000269|PubMed:12194985" FT MUTAGEN 231 FT /note="S->D: No effect on sorting from the ER to the FT vesicles, redistribution to apical membrane, or FT endocytosis." FT /evidence="ECO:0000269|PubMed:12194985" FT MUTAGEN 232 FT /note="E->A: Reduces interaction with MIAC." FT /evidence="ECO:0000269|PubMed:36117171" FT MUTAGEN 244 FT /note="T->A: No effect on sorting from the ER to the FT vesicles, redistribution to apical membrane, or FT endocytosis." FT /evidence="ECO:0000269|PubMed:12194985" FT MUTAGEN 244 FT /note="T->E: No effect on sorting from the ER to the FT vesicles, redistribution to apical membrane, or FT endocytosis." FT /evidence="ECO:0000269|PubMed:12194985" FT MUTAGEN 256 FT /note="S->A: Retained in vesicles." FT /evidence="ECO:0000269|PubMed:12194985" FT MUTAGEN 256 FT /note="S->D: Expressed in the apical membrane." FT /evidence="ECO:0000269|PubMed:12194985" FT MUTAGEN 262 FT /note="P->A: No effect on expression at the apical cell FT membrane." FT /evidence="ECO:0000269|PubMed:15509592" FT CONFLICT 35..38 FT /note="PQAL -> ATAP (in Ref. 4)" FT /evidence="ECO:0000305" FT CONFLICT 83 FT /note="V -> F (in Ref. 4)" FT /evidence="ECO:0000305" FT HELIX 7..32 FT /evidence="ECO:0007829|PDB:4NEF" FT STRAND 35..37 FT /evidence="ECO:0007829|PDB:4NEF" FT HELIX 41..63 FT /evidence="ECO:0007829|PDB:4NEF" FT HELIX 69..77 FT /evidence="ECO:0007829|PDB:4NEF" FT HELIX 83..107 FT /evidence="ECO:0007829|PDB:4NEF" FT HELIX 110..113 FT /evidence="ECO:0007829|PDB:4NEF" FT HELIX 127..148 FT /evidence="ECO:0007829|PDB:4NEF" FT HELIX 151..153 FT /evidence="ECO:0007829|PDB:8GCL" FT HELIX 159..179 FT /evidence="ECO:0007829|PDB:4NEF" FT HELIX 185..195 FT /evidence="ECO:0007829|PDB:4NEF" FT TURN 199..202 FT /evidence="ECO:0007829|PDB:4NEF" FT HELIX 203..221 FT /evidence="ECO:0007829|PDB:4NEF" FT HELIX 232..237 FT /evidence="ECO:0007829|PDB:4NEF" SQ SEQUENCE 271 AA; 28837 MW; C2DDE2AF4DDD192A CRC64; MWELRSIAFS RAVFAEFLAT LLFVFFGLGS ALNWPQALPS VLQIAMAFGL GIGTLVQALG HISGAHINPA VTVACLVGCH VSVLRAAFYV AAQLLGAVAG AALLHEITPA DIRGDLAVNA LSNSTTAGQA VTVELFLTLQ LVLCIFASTD ERRGENPGTP ALSIGFSVAL GHLLGIHYTG CSMNPARSLA PAVVTGKFDD HWVFWIGPLV GAILGSLLYN YVLFPPAKSL SERLAVLKGL EPDTDWEERE VRRRQSVELH SPQSLPRGTK A //