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 17-JUN-2020, entry version 178. 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; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC 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 human RT mercurial insensitive water channel. Evidence for distinct transcriptional RT units."; RL J. Biol. Chem. 270:22907-22913(1995). RN [2] {ECO:0000312|EMBL:BAA09715.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, SUBCELLULAR LOCATION, AND RP 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 in RT 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., Merkx G., RA Rijss J.P.L., Deen P.M.T.; RT "The human AQP4 gene: definition of the locus encoding two water channel RT 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., Taylor T.D., RA Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., RA Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J., RA Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L., RA Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., RA Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., RA Noguchi H., 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 project: RT 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., 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 pathological RT 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 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 a CC normal rate of water exchange across the blood brain interface. CC Required for normal levels of cerebrospinal fluid influx into the brain CC cortex and parenchyma along paravascular spaces that surround CC penetrating arteries, and for normal drainage of interstitial fluid CC along paravenous drainage pathways. Thereby, it is required for normal CC clearance of solutes from the brain interstitial fluid, including CC soluble beta-amyloid peptides derived from APP. Plays a redundant role CC in urinary water homeostasis and urinary concentrating ability (By CC similarity). {ECO:0000250|UniProtKB:P55088, CC ECO:0000269|PubMed:19383790, ECO:0000269|PubMed:7559426, CC 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 complex CC containing MLC1, TRPV4, HEPACAM and ATP1B1 (PubMed:22328087). CC {ECO:0000250|UniProtKB:P47863, ECO:0000269|PubMed:19383790, CC ECO:0000269|PubMed:22328087}. CC -!- INTERACTION: CC P55087; O43889-2: CREB3; NbExp=3; IntAct=EBI-10104898, EBI-625022; CC P55087; P48165: GJA8; NbExp=3; IntAct=EBI-10104898, EBI-17458373; CC P55087; Q9UM19: HPCAL4; NbExp=3; IntAct=EBI-10104898, EBI-744820; CC P55087-1; P55087-1: AQP4; NbExp=2; IntAct=EBI-15771758, EBI-15771758; 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 promotes CC its internalization from the cell membrane. Detected on brain astrocyte CC processes and astrocyte endfeet close to capillaries. CC {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 and CC 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 three CC membrane-spanning domains and a pore-forming loop with the signature CC 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 increases CC conductance by 40% (By similarity). {ECO:0000250}. CC -!- PTM: Isoform 2: Palmitoylated on its N-terminal region. Isoform 1: Not CC 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=Extended N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC 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; 4. 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 MassIVE; P55087; -. DR PaxDb; P55087; -. DR PeptideAtlas; P55087; -. DR PRIDE; P55087; -. DR ProteomicsDB; 56788; -. [P55087-1] DR ProteomicsDB; 56789; -. [P55087-2] DR Antibodypedia; 3103; 539 antibodies. 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 Ensembl; ENST00000672188; ENSP00000500720; ENSG00000171885. [P55087-1] DR GeneID; 361; -. DR KEGG; hsa:361; -. DR UCSC; uc002kvz.4; human. [P55087-1] DR CTD; 361; -. DR DisGeNET; 361; -. DR EuPathDB; HostDB:ENSG00000171885.13; -. DR GeneCards; AQP4; -. DR HGNC; HGNC:637; AQP4. DR HPA; ENSG00000171885; Group enriched (brain, lung). 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 InParanoid; P55087; -. DR KO; K09866; -. DR OMA; NWGGSEK; -. 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 BioGRID-ORCS; 361; 0 hits in 779 CRISPR screens. DR ChiTaRS; AQP4; human. DR EvolutionaryTrace; P55087; -. DR GeneWiki; Aquaporin_4; -. DR GenomeRNAi; 361; -. DR Pharos; P55087; Tbio. DR PRO; PR:P55087; -. DR Proteomes; UP000005640; Chromosome 18. DR RNAct; P55087; protein. DR Bgee; ENSG00000171885; Expressed in lateral globus pallidus and 153 other tissues. 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:0005623; C:cell; IEA:GOC. 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:0005576; C:extracellular region; IEA:GOC. 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 Endosome; Glycoprotein; Lipoprotein; Membrane; Palmitate; Phosphoprotein; KW Reference proteome; Repeat; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..323 FT /note="Aquaporin-4" FT /id="PRO_0000063948" FT TOPO_DOM 1..36 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:19383790" FT TRANSMEM 37..57 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:19383790" FT TOPO_DOM 58..69 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:19383790" FT TRANSMEM 70..89 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:19383790" FT TOPO_DOM 90..93 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:19383790" FT INTRAMEM 94..101 FT /note="Discontinuously helical" FT /evidence="ECO:0000269|PubMed:19383790" FT TOPO_DOM 102..115 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:19383790" FT TRANSMEM 116..136 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:19383790" FT TOPO_DOM 137..155 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:19383790" FT TRANSMEM 156..176 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:19383790" FT TOPO_DOM 177..184 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:19383790" FT TRANSMEM 185..205 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:19383790" FT TOPO_DOM 206..208 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:19383790" FT INTRAMEM 209..222 FT /note="Discontinuously helical" FT /evidence="ECO:0000269|PubMed:19383790" FT TOPO_DOM 223..231 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:19383790" FT TRANSMEM 232..252 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:19383790" FT TOPO_DOM 253..323 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:19383790" FT MOTIF 97..99 FT /note="NPA 1" FT /evidence="ECO:0000305|PubMed:19383790" FT MOTIF 213..215 FT /note="NPA 2" FT /evidence="ECO:0000305|PubMed:19383790" FT MOD_RES 111 FT /note="Phosphoserine; by PKG" FT /evidence="ECO:0000250|UniProtKB:P55088" FT MOD_RES 180 FT /note="Phosphoserine; by PKC" FT /evidence="ECO:0000250|UniProtKB:P47863" FT MOD_RES 276 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P47863" FT MOD_RES 285 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P55088" FT MOD_RES 289 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P55088" FT MOD_RES 321 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P47863" FT LIPID 13 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250|UniProtKB:P47863" FT LIPID 17 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000250|UniProtKB:P47863" FT CARBOHYD 153 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 206 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 1..22 FT /note="Missing (in isoform 1)" FT /evidence="ECO:0000305" FT /id="VSP_003232" FT CONFLICT 246 FT /note="G -> A (in Ref. 1; AAC52112)" FT /evidence="ECO:0000305" FT CONFLICT 287..288 FT /note="VE -> AK (in Ref. 1; AAC52112)" FT /evidence="ECO:0000305" FT CONFLICT 296 FT /note="P -> L (in Ref. 1; AAC52112)" FT /evidence="ECO:0000305" FT HELIX 33..55 FT /evidence="ECO:0000244|PDB:3GD8" FT TURN 59..63 FT /evidence="ECO:0000244|PDB:3GD8" FT HELIX 70..92 FT /evidence="ECO:0000244|PDB:3GD8" FT HELIX 98..106 FT /evidence="ECO:0000244|PDB:3GD8" FT HELIX 112..136 FT /evidence="ECO:0000244|PDB:3GD8" FT HELIX 139..142 FT /evidence="ECO:0000244|PDB:3GD8" FT TURN 143..146 FT /evidence="ECO:0000244|PDB:3GD8" FT HELIX 156..177 FT /evidence="ECO:0000244|PDB:3GD8" FT HELIX 189..208 FT /evidence="ECO:0000244|PDB:3GD8" FT HELIX 214..224 FT /evidence="ECO:0000244|PDB:3GD8" FT TURN 228..231 FT /evidence="ECO:0000244|PDB:3GD8" FT HELIX 232..250 FT /evidence="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 //