ID AQP4_HUMAN Reviewed; 323 AA. AC P55087; P78564; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1997, sequence version 2. DT 05-JUN-2019, entry version 169. DE RecName: Full=Aquaporin-4; DE Short=AQP-4; DE AltName: Full=Mercurial-insensitive water channel {ECO:0000303|PubMed:7559426}; DE Short=MIWC {ECO:0000303|PubMed:7559426}; DE AltName: Full=WCH4; GN Name=AQP4; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] {ECO:0000312|EMBL:AAC50284.1, ECO:0000312|EMBL:AAC52112.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, SUBCELLULAR RP LOCATION, AND TISSUE SPECIFICITY. RC TISSUE=Fetal brain; RX PubMed=7559426; DOI=10.1074/jbc.270.39.22907; RA Yang B., Ma T., Verkman A.S.; RT "cDNA cloning, gene organization, and chromosomal localization of a RT human mercurial insensitive water channel. Evidence for distinct RT transcriptional units."; RL J. Biol. Chem. 270:22907-22913(1995). RN [2] {ECO:0000312|EMBL:BAA09715.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, SUBCELLULAR RP LOCATION, AND TISSUE SPECIFICITY. RX PubMed=8601457; DOI=10.1016/0014-5793(96)00092-0; RA Misaka T., Abe K., Iwabuchi K., Kusakabe Y., Ichinose M., Miki K., RA Emori Y., Arai S.; RT "A water channel closely related to rat brain aquaporin 4 is expressed RT in acid- and pepsinogen-secretory cells of human stomach."; RL FEBS Lett. 381:208-212(1996). RN [3] {ECO:0000312|EMBL:AAB26957.1, ECO:0000312|EMBL:AAB26958.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). RX PubMed=8855281; DOI=10.1073/pnas.93.20.10908; RA Lu M., Lee M.D., Smith B.L., Jung J.S., Agre P., Verdijk M.A.J., RA Merkx G., Rijss J.P.L., Deen P.M.T.; RT "The human AQP4 gene: definition of the locus encoding two water RT channel polypeptides in brain."; RL Proc. Natl. Acad. Sci. U.S.A. 93:10908-10912(1996). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16177791; DOI=10.1038/nature03983; RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., RA Taylor T.D., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., RA FitzGerald M.G., Yang X., Abouelleil A., Allen N.R., Anderson S., RA Bloom T., Bugalter B., Butler J., Cook A., DeCaprio D., Engels R., RA Garber M., Gnirke A., Hafez N., Hall J.L., Norman C.H., Itoh T., RA Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., Macdonald P., Mauceli E., RA Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., Noguchi H., RA O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K., RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R., RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.; RT "DNA sequence and analysis of human chromosome 18."; RL Nature 437:551-555(2005). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Lung; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP SUBUNIT. RX PubMed=22328087; DOI=10.1093/hmg/dds032; RA Lanciotti A., Brignone M.S., Molinari P., Visentin S., De Nuccio C., RA Macchia G., Aiello C., Bertini E., Aloisi F., Petrucci T.C., RA Ambrosini E.; RT "Megalencephalic leukoencephalopathy with subcortical cysts protein 1 RT functionally cooperates with the TRPV4 cation channel to activate the RT response of astrocytes to osmotic stress: dysregulation by RT pathological mutations."; RL Hum. Mol. Genet. 21:2166-2180(2012). RN [7] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=29055082; DOI=10.1111/jcmm.13401; RA Rosito S., Nicchia G.P., Palazzo C., Lia A., Buccoliero C., Pisani F., RA Svelto M., Trojano M., Frigeri A.; RT "Supramolecular aggregation of aquaporin-4 is different in muscle and RT brain: correlation with tissue susceptibility in neuromyelitis RT optica."; RL J. Cell. Mol. Med. 22:1236-1246(2018). RN [8] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 32-254, FUNCTION, TOPOLOGY, RP SUBUNIT, AND DOMAIN. RX PubMed=19383790; DOI=10.1073/pnas.0902725106; RA Ho J.D., Yeh R., Sandstrom A., Chorny I., Harries W.E., Robbins R.A., RA Miercke L.J., Stroud R.M.; RT "Crystal structure of human aquaporin 4 at 1.8 A and its mechanism of RT conductance."; RL Proc. Natl. Acad. Sci. U.S.A. 106:7437-7442(2009). CC -!- FUNCTION: Forms a water-specific channel (PubMed:7559426, CC PubMed:8601457, PubMed:19383790). Plays an important role in brain CC water homeostasis and in glymphatic solute transport. Required for CC a normal rate of water exchange across the blood brain interface. CC Required for normal levels of cerebrospinal fluid influx into the CC brain cortex and parenchyma along paravascular spaces that CC surround penetrating arteries, and for normal drainage of CC interstitial fluid along paravenous drainage pathways. Thereby, it CC is required for normal clearance of solutes from the brain CC interstitial fluid, including soluble beta-amyloid peptides CC derived from APP. Plays a redundant role in urinary water CC homeostasis and urinary concentrating ability (By similarity). CC {ECO:0000250|UniProtKB:P55088, ECO:0000269|PubMed:19383790, CC ECO:0000269|PubMed:7559426, ECO:0000269|PubMed:8601457}. CC -!- SUBUNIT: Homotetramer (PubMed:19383790). The tetramers can form CC oligomeric arrays in membranes. The size of the oligomers differs CC between tissues and is smaller in skeletal muscle than in brain. CC Interaction between AQP4 oligomeric arrays in close-by cells can CC contribute to cell-cell adhesion (By similarity). Part of a CC complex containing MLC1, TRPV4, HEPACAM and ATP1B1 CC (PubMed:22328087). {ECO:0000250|UniProtKB:P47863, CC ECO:0000269|PubMed:19383790, ECO:0000269|PubMed:22328087}. CC -!- INTERACTION: CC O43889-2:CREB3; NbExp=3; IntAct=EBI-10104898, EBI-625022; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:7559426, CC ECO:0000269|PubMed:8601457}; Multi-pass membrane protein CC {ECO:0000269|PubMed:19383790}. Basolateral cell membrane CC {ECO:0000250|UniProtKB:P55088}; Multi-pass membrane protein CC {ECO:0000269|PubMed:19383790}. Endosome membrane CC {ECO:0000250|UniProtKB:P47863}. Cell membrane, sarcolemma CC {ECO:0000269|PubMed:29055082}; Multi-pass membrane protein CC {ECO:0000269|PubMed:19383790}. Cell projection CC {ECO:0000250|UniProtKB:P47863}. Note=Activation of the vasopressin CC receptor AVPR1A triggers AQP4 phosphorylation at Ser-180 and CC promotes its internalization from the cell membrane. Detected on CC brain astrocyte processes and astrocyte endfeet close to CC capillaries. {ECO:0000250|UniProtKB:P47863}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=2; Synonyms=AQP4-M1 {ECO:0000305}; CC IsoId=P55087-1; Sequence=Displayed; CC Name=1; Synonyms=AQP4-M23 {ECO:0000305}; CC IsoId=P55087-2; Sequence=VSP_003232; CC -!- TISSUE SPECIFICITY: Detected in skeletal muscle (PubMed:29055082). CC Detected in stomach, along the glandular base region of the fundic CC gland (at protein level) (PubMed:8601457). Detected in brain, lung CC and skeletal muscle, and at much lower levels in heart and ovary CC (PubMed:7559426, PubMed:8601457). {ECO:0000269|PubMed:29055082, CC ECO:0000269|PubMed:7559426, ECO:0000269|PubMed:8601457}. CC -!- DOMAIN: Aquaporins contain two tandem repeats each containing CC three membrane-spanning domains and a pore-forming loop with the CC signature motif Asn-Pro-Ala (NPA). {ECO:0000269|PubMed:19383790}. CC -!- PTM: Phosphorylation by PKC at Ser-180 reduces conductance by 50%. CC Phosphorylation by PKG at Ser-111 in response to glutamate CC increases conductance by 40% (By similarity). {ECO:0000250}. CC -!- PTM: Isoform 2: Palmitoylated on its N-terminal region. Isoform 1: CC Not palmitoylated. {ECO:0000250|UniProtKB:P47863}. CC -!- SIMILARITY: Belongs to the MIP/aquaporin (TC 1.A.8) family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAC52112.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology CC and Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/AQP4ID684ch18q11.html"; 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; U34846; AAC52112.1; ALT_INIT; mRNA. DR EMBL; U34845; AAC50284.1; -; mRNA. DR EMBL; D63412; BAA09715.1; -; mRNA. DR EMBL; U63622; AAB26957.1; -; mRNA. DR EMBL; U63623; AAB26958.1; -; mRNA. DR EMBL; AC018371; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC022286; AAH22286.1; -; mRNA. DR CCDS; CCDS11889.1; -. [P55087-1] DR CCDS; CCDS58617.1; -. [P55087-2] DR PIR; I39178; I39178. DR RefSeq; NP_001641.1; NM_001650.5. [P55087-1] DR RefSeq; NP_004019.1; NM_004028.4. [P55087-2] DR PDB; 3GD8; X-ray; 1.80 A; A=32-254. DR PDBsum; 3GD8; -. DR SMR; P55087; -. DR BioGrid; 106857; 3. DR CORUM; P55087; -. DR DIP; DIP-48842N; -. DR IntAct; P55087; 3. DR STRING; 9606.ENSP00000372654; -. DR ChEMBL; CHEMBL5964; -. DR TCDB; 1.A.8.8.5; the major intrinsic protein (mip) family. DR iPTMnet; P55087; -. DR PhosphoSitePlus; P55087; -. DR SwissPalm; P55087; -. DR BioMuta; AQP4; -. DR DMDM; 2506859; -. DR PaxDb; P55087; -. DR PeptideAtlas; P55087; -. DR PRIDE; P55087; -. DR ProteomicsDB; 56788; -. DR ProteomicsDB; 56789; -. [P55087-2] DR DNASU; 361; -. DR Ensembl; ENST00000383168; ENSP00000372654; ENSG00000171885. [P55087-1] DR Ensembl; ENST00000440832; ENSP00000393121; ENSG00000171885. [P55087-2] DR Ensembl; ENST00000581374; ENSP00000462597; ENSG00000171885. [P55087-2] DR GeneID; 361; -. DR KEGG; hsa:361; -. DR UCSC; uc002kvz.4; human. [P55087-1] DR CTD; 361; -. DR DisGeNET; 361; -. DR GeneCards; AQP4; -. DR HGNC; HGNC:637; AQP4. DR HPA; CAB005079; -. DR HPA; CAB058689; -. DR HPA; HPA014784; -. DR MIM; 600308; gene. DR neXtProt; NX_P55087; -. DR OpenTargets; ENSG00000171885; -. DR PharmGKB; PA24922; -. DR eggNOG; KOG0223; Eukaryota. DR eggNOG; COG0580; LUCA. DR GeneTree; ENSGT00940000156037; -. DR HOGENOM; HOG000288286; -. DR InParanoid; P55087; -. DR KO; K09866; -. DR OMA; TQPFWKA; -. DR OrthoDB; 1152704at2759; -. DR PhylomeDB; P55087; -. DR TreeFam; TF312940; -. DR Reactome; R-HSA-432040; Vasopressin regulates renal water homeostasis via Aquaporins. DR Reactome; R-HSA-432047; Passive transport by Aquaporins. DR SIGNOR; P55087; -. DR ChiTaRS; AQP4; human. DR EvolutionaryTrace; P55087; -. DR GeneWiki; Aquaporin_4; -. DR GenomeRNAi; 361; -. DR PRO; PR:P55087; -. DR Proteomes; UP000005640; Chromosome 18. DR Bgee; ENSG00000171885; Expressed in 154 organ(s), highest expression level in lateral globus pallidus. DR ExpressionAtlas; P55087; baseline and differential. DR Genevisible; P55087; HS. DR GO; GO:0097450; C:astrocyte end-foot; ISS:UniProtKB. DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0009897; C:external side of plasma membrane; IDA:UniProtKB. DR GO; GO:0016021; C:integral component of membrane; IBA:GO_Central. DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0042383; C:sarcolemma; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0015250; F:water channel activity; IDA:UniProtKB. DR GO; GO:0071346; P:cellular response to interferon-gamma; IDA:UniProtKB. DR GO; GO:0009992; P:cellular water homeostasis; ISS:UniProtKB. DR GO; GO:0090660; P:cerebrospinal fluid circulation; ISS:UniProtKB. DR GO; GO:0050891; P:multicellular organismal water homeostasis; IEP:UniProtKB. DR GO; GO:0051289; P:protein homotetramerization; IDA:UniProtKB. DR GO; GO:0003091; P:renal water homeostasis; TAS:Reactome. DR GO; GO:0030104; P:water homeostasis; ISS:UniProtKB. DR GO; GO:0006833; P:water transport; IDA:UniProtKB. DR CDD; cd00333; MIP; 1. DR Gene3D; 1.20.1080.10; -; 1. DR InterPro; IPR023271; Aquaporin-like. DR InterPro; IPR034294; Aquaporin_transptr. DR InterPro; IPR000425; MIP. DR InterPro; IPR022357; MIP_CS. DR PANTHER; PTHR19139; PTHR19139; 1. DR Pfam; PF00230; MIP; 1. DR PRINTS; PR00783; MINTRINSICP. DR SUPFAM; SSF81338; SSF81338; 1. DR TIGRFAMs; TIGR00861; MIP; 1. DR PROSITE; PS00221; MIP; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cell projection; KW Complete proteome; Endosome; Glycoprotein; Lipoprotein; Membrane; KW Palmitate; Phosphoprotein; Reference proteome; Repeat; Transmembrane; KW Transmembrane helix; Transport. FT CHAIN 1 323 Aquaporin-4. FT /FTId=PRO_0000063948. FT TOPO_DOM 1 36 Cytoplasmic. FT {ECO:0000269|PubMed:19383790}. FT TRANSMEM 37 57 Helical. {ECO:0000269|PubMed:19383790}. FT TOPO_DOM 58 69 Extracellular. FT {ECO:0000269|PubMed:19383790}. FT TRANSMEM 70 89 Helical. {ECO:0000269|PubMed:19383790}. FT TOPO_DOM 90 93 Cytoplasmic. FT {ECO:0000269|PubMed:19383790}. FT INTRAMEM 94 101 Discontinuously helical. FT {ECO:0000269|PubMed:19383790}. FT TOPO_DOM 102 115 Cytoplasmic. FT {ECO:0000269|PubMed:19383790}. FT TRANSMEM 116 136 Helical. {ECO:0000269|PubMed:19383790}. FT TOPO_DOM 137 155 Extracellular. FT {ECO:0000269|PubMed:19383790}. FT TRANSMEM 156 176 Helical. {ECO:0000269|PubMed:19383790}. FT TOPO_DOM 177 184 Cytoplasmic. FT {ECO:0000269|PubMed:19383790}. FT TRANSMEM 185 205 Helical. {ECO:0000269|PubMed:19383790}. FT TOPO_DOM 206 208 Extracellular. FT {ECO:0000269|PubMed:19383790}. FT INTRAMEM 209 222 Discontinuously helical. FT {ECO:0000269|PubMed:19383790}. FT TOPO_DOM 223 231 Extracellular. FT {ECO:0000269|PubMed:19383790}. FT TRANSMEM 232 252 Helical. {ECO:0000269|PubMed:19383790}. FT TOPO_DOM 253 323 Cytoplasmic. FT {ECO:0000269|PubMed:19383790}. FT MOTIF 97 99 NPA 1. {ECO:0000305|PubMed:19383790}. FT MOTIF 213 215 NPA 2. {ECO:0000305|PubMed:19383790}. FT MOD_RES 111 111 Phosphoserine; by PKG. FT {ECO:0000250|UniProtKB:P55088}. FT MOD_RES 180 180 Phosphoserine; by PKC. FT {ECO:0000250|UniProtKB:P47863}. FT MOD_RES 276 276 Phosphoserine. FT {ECO:0000250|UniProtKB:P47863}. FT MOD_RES 285 285 Phosphoserine. FT {ECO:0000250|UniProtKB:P55088}. FT MOD_RES 289 289 Phosphothreonine. FT {ECO:0000250|UniProtKB:P55088}. FT MOD_RES 321 321 Phosphoserine. FT {ECO:0000250|UniProtKB:P47863}. FT LIPID 13 13 S-palmitoyl cysteine. FT {ECO:0000250|UniProtKB:P47863}. FT LIPID 17 17 S-palmitoyl cysteine. FT {ECO:0000250|UniProtKB:P47863}. FT CARBOHYD 153 153 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 206 206 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT VAR_SEQ 1 22 Missing (in isoform 1). {ECO:0000305}. FT /FTId=VSP_003232. FT CONFLICT 246 246 G -> A (in Ref. 1; AAC52112). FT {ECO:0000305}. FT CONFLICT 287 288 VE -> AK (in Ref. 1; AAC52112). FT {ECO:0000305}. FT CONFLICT 296 296 P -> L (in Ref. 1; AAC52112). FT {ECO:0000305}. FT HELIX 33 55 {ECO:0000244|PDB:3GD8}. FT TURN 59 63 {ECO:0000244|PDB:3GD8}. FT HELIX 70 92 {ECO:0000244|PDB:3GD8}. FT HELIX 98 106 {ECO:0000244|PDB:3GD8}. FT HELIX 112 136 {ECO:0000244|PDB:3GD8}. FT HELIX 139 142 {ECO:0000244|PDB:3GD8}. FT TURN 143 146 {ECO:0000244|PDB:3GD8}. FT HELIX 156 177 {ECO:0000244|PDB:3GD8}. FT HELIX 189 208 {ECO:0000244|PDB:3GD8}. FT HELIX 214 224 {ECO:0000244|PDB:3GD8}. FT TURN 228 231 {ECO:0000244|PDB:3GD8}. FT HELIX 232 250 {ECO:0000244|PDB:3GD8}. SQ SEQUENCE 323 AA; 34830 MW; 1A1600CF0DC11052 CRC64; MSDRPTARRW GKCGPLCTRE NIMVAFKGVW TQAFWKAVTA EFLAMLIFVL LSLGSTINWG GTEKPLPVDM VLISLCFGLS IATMVQCFGH ISGGHINPAV TVAMVCTRKI SIAKSVFYIA AQCLGAIIGA GILYLVTPPS VVGGLGVTMV HGNLTAGHGL LVELIITFQL VFTIFASCDS KRTDVTGSIA LAIGFSVAIG HLFAINYTGA SMNPARSFGP AVIMGNWENH WIYWVGPIIG AVLAGGLYEY VFCPDVEFKR RFKEAFSKAA QQTKGSYMEV EDNRSQVETD DLILKPGVVH VIDVDRGEEK KGKDQSGEVL SSV //