ID MCLN3_HUMAN Reviewed; 553 AA. AC Q8TDD5; Q5T4H5; Q5T4H6; Q9NV09; DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2002, sequence version 1. DT 27-MAR-2024, entry version 164. DE RecName: Full=Mucolipin-3 {ECO:0000303|PubMed:19497048}; DE AltName: Full=Transient receptor potential channel mucolipin 3; DE Short=TRPML3 {ECO:0000303|PubMed:18369318}; GN Name=MCOLN3; 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 [MRNA] (ISOFORM 1). RA Falardeau J.L., Kennedy J.C., Acierno J.S. Jr., Slaugenhaupt S.A.; RT "Cloning of the MCOLN3 gene."; RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Placenta; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [4] RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF HIS-252; HIS-273; HIS-283 RP AND ALA-419. RX PubMed=18369318; DOI=10.1038/emboj.2008.56; RA Kim H.J., Li Q., Tjon-Kon-Sang S., So I., Kiselyov K., Soyombo A.A., RA Muallem S.; RT "A novel mode of TRPML3 regulation by extracytosolic pH absent in the RT varitint-waddler phenotype."; RL EMBO J. 27:1197-1205(2008). RN [5] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=19497048; DOI=10.1111/j.1600-0854.2009.00935.x; RA Martina J.A., Lelouvier B., Puertollano R.; RT "The calcium channel mucolipin-3 is a novel regulator of trafficking along RT the endosomal pathway."; RL Traffic 10:1143-1156(2009). RN [6] RP FUNCTION, SUBCELLULAR LOCATION, GLYCOSYLATION, AND MUTAGENESIS OF ASP-458 RP AND 458-ASP-ASP-459. RX PubMed=19522758; DOI=10.1111/j.1600-0854.2009.00924.x; RA Kim H.J., Soyombo A.A., Tjon-Kon-Sang S., So I., Muallem S.; RT "The Ca(2+) channel TRPML3 regulates membrane trafficking and autophagy."; RL Traffic 10:1157-1167(2009). RN [7] RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF HIS-283; ALA-419; GLU-449 RP AND ASP-459. RX PubMed=20378547; DOI=10.1074/jbc.m109.078204; RA Kim H.J., Yamaguchi S., Li Q., So I., Muallem S.; RT "Properties of the TRPML3 channel pore and its stable expansion by the RT Varitint-Waddler-causing mutation."; RL J. Biol. Chem. 285:16513-16520(2010). RN [8] RP SUBUNIT, AND FUNCTION. RX PubMed=19885840; DOI=10.1002/jcp.21956; RA Curcio-Morelli C., Zhang P., Venugopal B., Charles F.A., Browning M.F., RA Cantiello H.F., Slaugenhaupt S.A.; RT "Functional multimerization of mucolipin channel proteins."; RL J. Cell. Physiol. 222:328-335(2010). RN [9] RP FUNCTION. RX PubMed=21245134; DOI=10.1074/jbc.m110.169185; RA Lelouvier B., Puertollano R.; RT "Mucolipin-3 regulates luminal calcium, acidification, and membrane fusion RT in the endosomal pathway."; RL J. Biol. Chem. 286:9826-9832(2011). RN [10] RP FUNCTION, AND SUBUNIT. RX PubMed=23469151; DOI=10.1371/journal.pone.0058174; RA Guo Z., Grimm C., Becker L., Ricci A.J., Heller S.; RT "A novel ion channel formed by interaction of TRPML3 with TRPV5."; RL PLoS ONE 8:E58174-E58174(2013). RN [11] RP STRUCTURE BY ELECTRON MICROSCOPY (3.62 ANGSTROMS), FUNCTION, ACTIVITY RP REGULATION, SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, GLYCOSYLATION AT RP ASN-138 AND ASN-172, AND MUTAGENESIS OF ASP-108; ASP-111; ASP-112; TYR-423 RP AND PHE-497. RX PubMed=29106414; DOI=10.1038/nsmb.3502; RA Zhou X., Li M., Su D., Jia Q., Li H., Li X., Yang J.; RT "Cryo-EM structures of the human endolysosomal TRPML3 channel in three RT distinct states."; RL Nat. Struct. Mol. Biol. 24:1146-1154(2017). CC -!- FUNCTION: Nonselective ligand-gated cation channel probably playing a CC role in the regulation of membrane trafficking events. Acts as a CC Ca(2+)-permeable cation channel with inwardly rectifying activity CC (PubMed:18369318, PubMed:19497048, PubMed:19522758, PubMed:19885840, CC PubMed:29106414). Mediates release of Ca(2+) from endosomes to the CC cytoplasm, contributes to endosomal acidification and is involved in CC the regulation of membrane trafficking and fusion in the endosomal CC pathway (PubMed:21245134). Does not seem to act as mechanosensory CC transduction channel in inner ear sensory hair cells. Proposed to play CC a critical role at the cochlear stereocilia ankle-link region during CC hair-bundle growth (By similarity). Involved in the regulation of CC autophagy (PubMed:19522758). Through association with GABARAPL2 may be CC involved in autophagosome formation possibly providing Ca(2+) for the CC fusion process (By similarity). Through a possible and probably tissue- CC specific heteromerization with MCOLN1 may be at least in part involved CC in many lysosome-dependent cellular events (PubMed:19885840). Possible CC heteromeric ion channel assemblies with TRPV5 show pharmacological CC similarity with TRPML3 (PubMed:23469151). CC {ECO:0000250|UniProtKB:Q8R4F0, ECO:0000269|PubMed:18369318, CC ECO:0000269|PubMed:19497048, ECO:0000269|PubMed:19522758, CC ECO:0000269|PubMed:19885840, ECO:0000269|PubMed:20378547, CC ECO:0000269|PubMed:21245134, ECO:0000269|PubMed:23469151, CC ECO:0000269|PubMed:29106414, ECO:0000305}. CC -!- ACTIVITY REGULATION: Inhibited by lumenal H(+) and Na(+) CC (PubMed:18369318, PubMed:29106414). The channel pore shows dynamic CC behavior and undergoes spontaneous, Ca(2+)-dependent modulation when CC conducting Ca(2+) (PubMed:20378547). {ECO:0000269|PubMed:18369318, CC ECO:0000269|PubMed:20378547, ECO:0000269|PubMed:29106414}. CC -!- SUBUNIT: Homotetramer (PubMed:29106414). Can heterooligomerize with CC MCOLN1; heteromeric assemblies have different channel properties as CC compared to the respective homooligomers and may be tissue-specific CC (PubMed:19885840). May heterooligomerize with TRPV5 to form a CC functional distinct ion channel (PubMed:23469151). Interacts with CC GABARAPL2 (By similarity). {ECO:0000250|UniProtKB:Q8R4F0, CC ECO:0000269|PubMed:19885840, ECO:0000269|PubMed:29106414, CC ECO:0000305|PubMed:23469151}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:19522758, CC ECO:0000269|PubMed:29106414}; Multi-pass membrane protein CC {ECO:0000269|PubMed:29106414}. Early endosome membrane CC {ECO:0000269|PubMed:19497048, ECO:0000269|PubMed:19522758}; Multi-pass CC membrane protein {ECO:0000269|PubMed:29106414}. Late endosome membrane CC {ECO:0000269|PubMed:19497048, ECO:0000269|PubMed:19522758}; Multi-pass CC membrane protein {ECO:0000269|PubMed:29106414}. Lysosome membrane CC {ECO:0000269|PubMed:19522758}; Multi-pass membrane protein CC {ECO:0000269|PubMed:29106414}. Cytoplasmic vesicle, autophagosome CC membrane {ECO:0000269|PubMed:19522758}. Note=Recycles between the CC plasma membrane and intracellular compartments by a dynamin-dependent CC endocytic pathway (PubMed:19522758). Under normal conditions, only a CC very minor proportion is present at the cell membrane CC (PubMed:19522758). In the cochlea located at the base of stereocilia CC near the position of the ankle links (By similarity). CC {ECO:0000250|UniProtKB:Q8R4F0, ECO:0000269|PubMed:19522758}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q8TDD5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8TDD5-2; Sequence=VSP_010823; CC -!- DOMAIN: The most N-terminal extracellular/lumenal domain (referred to CC as I-II linker or polycystin-mucolipin domain) contributes to a CC structure with a four-fold rotational symmetry in a tetrameric CC assembly; the structure contains a central highly electronegative pore CC with a 14 A diameter. The pore is critical for Ca(2+) and pH CC regulation. The protruding structure formed by the I-II linkers may CC contain all the interaction sites with lipids and proteins in the CC endolysosomal lumen. {ECO:0000250|UniProtKB:Q9GZU1}. CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:19885840}. CC -!- SIMILARITY: Belongs to the transient receptor (TC 1.A.4) family. CC Polycystin subfamily. MCOLN3 sub-subfamily. {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; AF475085; AAL84622.1; -; mRNA. DR EMBL; AK001868; BAA91951.1; -; mRNA. DR EMBL; AL358789; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS58009.1; -. [Q8TDD5-2] DR CCDS; CCDS701.1; -. [Q8TDD5-1] DR RefSeq; NP_001240622.1; NM_001253693.1. [Q8TDD5-2] DR RefSeq; NP_060768.8; NM_018298.10. [Q8TDD5-1] DR RefSeq; XP_005271060.1; XM_005271003.1. [Q8TDD5-1] DR RefSeq; XP_006710813.1; XM_006710750.1. DR PDB; 6AYE; EM; 4.06 A; A/B/C/D=1-553. DR PDB; 6AYF; EM; 3.62 A; A/B/C/D=1-553. DR PDB; 6AYG; EM; 4.65 A; A/B/C/D=1-553. DR PDBsum; 6AYE; -. DR PDBsum; 6AYF; -. DR PDBsum; 6AYG; -. DR AlphaFoldDB; Q8TDD5; -. DR EMDB; EMD-7018; -. DR EMDB; EMD-7019; -. DR EMDB; EMD-7020; -. DR SMR; Q8TDD5; -. DR BioGRID; 120571; 68. DR IntAct; Q8TDD5; 42. DR STRING; 9606.ENSP00000359621; -. DR BindingDB; Q8TDD5; -. DR ChEMBL; CHEMBL1293243; -. DR GuidetoPHARMACOLOGY; 503; -. DR TCDB; 1.A.5.3.4; the polycystin cation channel (pcc) family. DR GlyConnect; 1522; 2 N-Linked glycans (1 site). DR GlyCosmos; Q8TDD5; 3 sites, 2 glycans. DR GlyGen; Q8TDD5; 4 sites, 2 N-linked glycans (1 site). DR iPTMnet; Q8TDD5; -. DR PhosphoSitePlus; Q8TDD5; -. DR SwissPalm; Q8TDD5; -. DR BioMuta; MCOLN3; -. DR DMDM; 50401084; -. DR EPD; Q8TDD5; -. DR jPOST; Q8TDD5; -. DR MassIVE; Q8TDD5; -. DR MaxQB; Q8TDD5; -. DR PaxDb; 9606-ENSP00000359621; -. DR PeptideAtlas; Q8TDD5; -. DR ProteomicsDB; 74270; -. [Q8TDD5-1] DR ProteomicsDB; 74271; -. [Q8TDD5-2] DR ABCD; Q8TDD5; 1 sequenced antibody. DR Antibodypedia; 19787; 184 antibodies from 29 providers. DR DNASU; 55283; -. DR Ensembl; ENST00000341115.8; ENSP00000342698.3; ENSG00000055732.13. [Q8TDD5-2] DR Ensembl; ENST00000370589.7; ENSP00000359621.1; ENSG00000055732.13. [Q8TDD5-1] DR GeneID; 55283; -. DR KEGG; hsa:55283; -. DR MANE-Select; ENST00000370589.7; ENSP00000359621.1; NM_018298.11; NP_060768.8. DR UCSC; uc001dkp.4; human. [Q8TDD5-1] DR AGR; HGNC:13358; -. DR CTD; 55283; -. DR DisGeNET; 55283; -. DR GeneCards; MCOLN3; -. DR HGNC; HGNC:13358; MCOLN3. DR HPA; ENSG00000055732; Group enriched (adrenal gland, epididymis, parathyroid gland). DR MIM; 607400; gene. DR neXtProt; NX_Q8TDD5; -. DR OpenTargets; ENSG00000055732; -. DR PharmGKB; PA134947324; -. DR VEuPathDB; HostDB:ENSG00000055732; -. DR eggNOG; KOG3733; Eukaryota. DR GeneTree; ENSGT00950000183036; -. DR HOGENOM; CLU_020945_1_1_1; -. DR InParanoid; Q8TDD5; -. DR OMA; WQARRKF; -. DR OrthoDB; 2877219at2759; -. DR PhylomeDB; Q8TDD5; -. DR TreeFam; TF317783; -. DR PathwayCommons; Q8TDD5; -. DR Reactome; R-HSA-3295583; TRP channels. DR SignaLink; Q8TDD5; -. DR BioGRID-ORCS; 55283; 15 hits in 1145 CRISPR screens. DR ChiTaRS; MCOLN3; human. DR GeneWiki; MCOLN3; -. DR GenomeRNAi; 55283; -. DR Pharos; Q8TDD5; Tchem. DR PRO; PR:Q8TDD5; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q8TDD5; Protein. DR Bgee; ENSG00000055732; Expressed in right adrenal gland cortex and 147 other cell types or tissues. DR ExpressionAtlas; Q8TDD5; baseline and differential. DR GO; GO:0000421; C:autophagosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005765; C:lysosomal membrane; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0005262; F:calcium channel activity; TAS:Reactome. DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW. DR GO; GO:0072345; F:NAADP-sensitive calcium-release channel activity; IBA:GO_Central. DR GO; GO:0070588; P:calcium ion transmembrane transport; TAS:Reactome. DR GO; GO:0042491; P:inner ear auditory receptor cell differentiation; IEA:Ensembl. DR GO; GO:0007626; P:locomotory behavior; IEA:Ensembl. DR CDD; cd21072; ELD_TRPML3; 1. DR Gene3D; 1.10.287.70; -; 1. DR InterPro; IPR049134; MCLN_ECD. DR InterPro; IPR047317; MCOLN3_ELD. DR InterPro; IPR039031; Mucolipin. DR InterPro; IPR013122; PKD1_2_channel. DR PANTHER; PTHR12127; MUCOLIPIN; 1. DR PANTHER; PTHR12127:SF5; MUCOLIPIN-3; 1. DR Pfam; PF21381; MCLN_ECD; 1. DR Pfam; PF08016; PKD_channel; 1. DR Genevisible; Q8TDD5; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cytoplasmic vesicle; KW Disulfide bond; Endosome; Glycoprotein; Ion channel; Ion transport; KW Lipid-binding; Lysosome; Membrane; Reference proteome; Transmembrane; KW Transmembrane helix; Transport. FT CHAIN 1..553 FT /note="Mucolipin-3" FT /id="PRO_0000215367" FT TOPO_DOM 1..62 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:29106414" FT TRANSMEM 63..83 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29106414" FT TOPO_DOM 84..283 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:29106414" FT TRANSMEM 284..304 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29106414" FT TOPO_DOM 305..341 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:29106414" FT TRANSMEM 342..362 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29106414" FT TOPO_DOM 363..371 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:29106414" FT TRANSMEM 372..392 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29106414" FT TOPO_DOM 393..414 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:29106414" FT TRANSMEM 415..435 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29106414" FT TOPO_DOM 436..443 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:29106414" FT INTRAMEM 444..464 FT /note="Pore-forming" FT /evidence="ECO:0000269|PubMed:29106414" FT TOPO_DOM 465..475 FT /note="Extracellular" FT /evidence="ECO:0000269|PubMed:29106414" FT TRANSMEM 476..497 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29106414" FT TOPO_DOM 498..553 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:29106414" FT REGION 52..62 FT /note="Interaction with phosphoinositides" FT /evidence="ECO:0000250|UniProtKB:F6RG56" FT REGION 104..118 FT /note="Extracellular/lumenal pore loop" FT /evidence="ECO:0000250|UniProtKB:Q9GZU1" FT MOTIF 456..459 FT /note="Selectivity filter" FT /evidence="ECO:0000269|PubMed:29106414" FT SITE 305 FT /note="Interaction with phosphoinositides" FT /evidence="ECO:0000250|UniProtKB:F6RG56" FT CARBOHYD 138 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:29106414" FT CARBOHYD 172 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:29106414" FT CARBOHYD 205 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 159..185 FT /evidence="ECO:0000250|UniProtKB:Q9GZU1" FT DISULFID 238..269 FT /evidence="ECO:0000250|UniProtKB:Q9GZU1" FT VAR_SEQ 77..132 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_010823" FT MUTAGEN 108 FT /note="D->N: Abolishes basal channel activity without FT affecting channel activation by a synthetic agonist; when FT associated with N-111 and N-112." FT /evidence="ECO:0000269|PubMed:29106414" FT MUTAGEN 111 FT /note="D->N: Abolishes basal channel activity without FT affecting channel activation by a synthetic agonist; when FT associated with N-108 and N-112." FT /evidence="ECO:0000269|PubMed:29106414" FT MUTAGEN 112 FT /note="D->N: Abolishes basal channel activity without FT affecting channel activation by a synthetic agonist; when FT associated with N-108 and N-111." FT /evidence="ECO:0000269|PubMed:29106414" FT MUTAGEN 252 FT /note="H->A: Increases inhibition by lumenal H(+). FT Decreases inhibition by lumenal H(+); when associated with FT A-283." FT /evidence="ECO:0000269|PubMed:18369318" FT MUTAGEN 273 FT /note="H->A: Increases inhibition by lumenal H(+). FT Decreases inhibition by lumenal H(+); when associated with FT A-283." FT /evidence="ECO:0000269|PubMed:18369318" FT MUTAGEN 283 FT /note="H->A: Constitutive active channel; abolishes FT inhibition by lumenal H(+); retains the Ca(2+)-dependent FT inactivation of the Ca(2+) current. Decreases inhibition by FT lumenal H(+); when associated with A-252. Decreases FT inhibition by lumenal H(+); when associated with A-273." FT /evidence="ECO:0000269|PubMed:18369318" FT MUTAGEN 283 FT /note="H->R: Increases inhibition by lumenal H(+)." FT /evidence="ECO:0000269|PubMed:18369318" FT MUTAGEN 419 FT /note="A->P: Constitutive active channel; abolishes FT inhibition by lumenal H(+); increases the pore diameter." FT /evidence="ECO:0000269|PubMed:18369318, FT ECO:0000269|PubMed:20378547" FT MUTAGEN 423 FT /note="Y->A: Nearly abolishes channel activation by a FT synthetic agonist." FT /evidence="ECO:0000269|PubMed:29106414" FT MUTAGEN 449 FT /note="E->A: Constitutive active channel; greatly impairs FT inhibition by lumenal Na(+)." FT /evidence="ECO:0000269|PubMed:20378547" FT MUTAGEN 449 FT /note="E->K: Abolishes channel activity." FT /evidence="ECO:0000269|PubMed:20378547" FT MUTAGEN 458..459 FT /note="DD->KK: Enhances endocytosis." FT /evidence="ECO:0000269|PubMed:19522758" FT MUTAGEN 458 FT /note="D->K: Nearly abolishes channel activity; inhibits FT starvation-induced autophagy." FT /evidence="ECO:0000269|PubMed:19522758" FT MUTAGEN 459 FT /note="D->A: Decreases in Ca(2+) permeability and FT selectivity; decreases channel pore dynamic behavior." FT /evidence="ECO:0000269|PubMed:20378547" FT MUTAGEN 497 FT /note="F->A: Nearly abolishes channel activation by a FT synthetic agonist." FT /evidence="ECO:0000269|PubMed:29106414" FT CONFLICT 9 FT /note="S -> C (in Ref. 2; BAA91951)" FT /evidence="ECO:0000305" SQ SEQUENCE 553 AA; 64248 MW; 2E63DA196379F9E3 CRC64; MADPEVVVSS CSSHEEENRC NFNQQTSPSE ELLLEDQMRR KLKFFFMNPC EKFWARGRKP WKLAIQILKI AMVTIQLVLF GLSNQMVVAF KEENTIAFKH LFLKGYMDRM DDTYAVYTQS DVYDQLIFAV NQYLQLYNVS VGNHAYENKG TKQSAMAICQ HFYKRGNIYP GNDTFDIDPE IETECFFVEP DEPFHIGTPA ENKLNLTLDF HRLLTVELQF KLKAINLQTV RHQELPDCYD FTLTITFDNK AHSGRIKISL DNDISIRECK DWHVSGSIQK NTHYMMIFDA FVILTCLVSL ILCIRSVIRG LQLQQEFVNF FLLHYKKEVS VSDQMEFVNG WYIMIIISDI LTIIGSILKM EIQAKSLTSY DVCSILLGTS TMLVWLGVIR YLGFFAKYNL LILTLQAALP NVIRFCCCAA MIYLGYCFCG WIVLGPYHDK FRSLNMVSEC LFSLINGDDM FATFAKMQQK SYLVWLFSRI YLYSFISLFI YMILSLFIAL ITDTYETIKQ YQQDGFPETE LRTFISECKD LPNSGKYRLE DDPPVSLFCC CKK //