ID TPC2_MOUSE Reviewed; 731 AA. AC Q8BWC0; Q6NSV0; Q8BTJ7; Q8R396; DT 06-FEB-2007, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2003, sequence version 1. DT 27-MAR-2024, entry version 148. DE RecName: Full=Two pore channel protein 2; DE AltName: Full=Two pore calcium channel protein 2 {ECO:0000305}; DE AltName: Full=Voltage-dependent calcium channel protein TPC2; GN Name=Tpcn2 {ECO:0000312|MGI:MGI:2385297}; Synonyms=Tpc2; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC STRAIN=C57BL/6J; TISSUE=Bone marrow, and Heart; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3). RC STRAIN=Czech II; TISSUE=Eye, and Mammary gland; 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 [3] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=19387438; DOI=10.1038/nature08030; RA Calcraft P.J., Ruas M., Pan Z., Cheng X., Arredouani A., Hao X., Tang J., RA Rietdorf K., Teboul L., Chuang K.T., Lin P., Xiao R., Wang C., Zhu Y., RA Lin Y., Wyatt C.N., Parrington J., Ma J., Evans A.M., Galione A., Zhu M.X.; RT "NAADP mobilizes calcium from acidic organelles through two-pore RT channels."; RL Nature 459:596-600(2009). RN [4] RP GLYCOSYLATION AT ASN-594 AND ASN-601, SUBCELLULAR LOCATION, SUBUNIT, TISSUE RP SPECIFICITY, TOPOLOGY, AND MUTAGENESIS OF ASN-594 AND ASN-601. RX PubMed=19557428; DOI=10.1007/s00424-009-0690-y; RA Zong X., Schieder M., Cuny H., Fenske S., Gruner C., Roetzer K., RA Griesbeck O., Harz H., Biel M., Wahl-Schott C.; RT "The two-pore channel TPCN2 mediates NAADP-dependent Ca(2+)-release from RT lysosomal stores."; RL Pflugers Arch. 458:891-899(2009). RN [5] RP FUNCTION, MUTAGENESIS OF ASN-257 AND GLU-643, AND SUBCELLULAR LOCATION. RX PubMed=20495006; DOI=10.1074/jbc.c110.143123; RA Schieder M., Roetzer K., Brueggemann A., Biel M., Wahl-Schott C.A.; RT "Characterizatgmion of two-pore channel 2 (TPCN2)-mediated Ca2+ currents in RT isolated lysosomes."; RL J. Biol. Chem. 285:21219-21222(2010). RN [6] RP FUNCTION. RX PubMed=20547763; DOI=10.1074/jbc.m110.129833; RA Tugba Durlu-Kandilci N., Ruas M., Chuang K.T., Brading A., Parrington J., RA Galione A.; RT "TPC2 proteins mediate nicotinic acid adenine dinucleotide phosphate RT (NAADP)- and agonist-evoked contractions of smooth muscle."; RL J. Biol. Chem. 285:24925-24932(2010). RN [7] RP FUNCTION. RX PubMed=23063126; DOI=10.1016/j.cell.2012.08.036; RA Wang X., Zhang X., Dong X.P., Samie M., Li X., Cheng X., Goschka A., RA Shen D., Zhou Y., Harlow J., Zhu M.X., Clapham D.E., Ren D., Xu H.; RT "TPC proteins are phosphoinositide- activated sodium-selective ion channels RT in endosomes and lysosomes."; RL Cell 151:372-383(2012). RN [8] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=23394946; DOI=10.1016/j.cell.2013.01.023; RA Cang C., Zhou Y., Navarro B., Seo Y.J., Aranda K., Shi L., RA Battaglia-Hsu S., Nissim I., Clapham D.E., Ren D.; RT "mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to RT metabolic state."; RL Cell 152:778-790(2013). RN [9] RP FUNCTION, DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, AND CATALYTIC RP ACTIVITY. RX PubMed=25144390; DOI=10.1038/ncomms5699; RA Grimm C., Holdt L.M., Chen C.C., Hassan S., Mueller C., Joers S., Cuny H., RA Kissing S., Schroeder B., Butz E., Northoff B., Castonguay J., Luber C.A., RA Moser M., Spahn S., Luellmann-Rauch R., Fendel C., Klugbauer N., RA Griesbeck O., Haas A., Mann M., Bracher F., Teupser D., Saftig P., Biel M., RA Wahl-Schott C.; RT "High susceptibility to fatty liver disease in two-pore channel 2-deficient RT mice."; RL Nat. Commun. 5:4699-4699(2014). RN [10] RP FUNCTION (MICROBIAL INFECTION). RX PubMed=25722412; DOI=10.1126/science.1258758; RA Sakurai Y., Kolokoltsov A.A., Chen C.C., Tidwell M.W., Bauta W.E., RA Klugbauer N., Grimm C., Wahl-Schott C., Biel M., Davey R.A.; RT "Ebola virus. Two-pore channels control Ebola virus host cell entry and are RT drug targets for disease treatment."; RL Science 347:995-998(2015). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=27231233; DOI=10.1038/srep26570; RA Bellono N.W., Escobar I.E., Oancea E.; RT "A melanosomal two-pore sodium channel regulates pigmentation."; RL Sci. Rep. 6:26570-26570(2016). RN [12] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=32167471; DOI=10.7554/elife.54712; RA Gerndt S., Chen C.C., Chao Y.K., Yuan Y., Burgstaller S., Scotto Rosato A., RA Krogsaeter E., Urban N., Jacob K., Nguyen O.N.P., Miller M.T., Keller M., RA Vollmar A.M., Gudermann T., Zierler S., Schredelseker J., Schaefer M., RA Biel M., Malli R., Wahl-Schott C., Bracher F., Patel S., Grimm C.; RT "Agonist-mediated switching of ion selectivity in TPC2 differentially RT promotes lysosomal function."; RL Elife 9:0-0(2020). CC -!- FUNCTION: Intracellular channel initially characterized as a non- CC selective Ca(2+)-permeable channel activated by NAADP (nicotinic acid CC adenine dinucleotide phosphate), it is also a highly-selective Na(+) CC channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5- CC bisphosphate) (PubMed:19387438, PubMed:20495006, PubMed:20547763, CC PubMed:25144390, PubMed:27231233). Localizes to the lysosomal and late CC endosome membranes where it regulates organellar membrane excitability, CC membrane trafficking, and pH homeostasis. Is associated with a plethora CC of physiological processes, including mTOR-dependent nutrient sensing, CC skin pigmentation and autophagy (PubMed:25144390, PubMed:23394946, CC PubMed:23063126). Ion selectivity is not fixed but rather agonist- CC dependent and under defined ionic conditions, can be readily activated CC by both NAADP and PI(3,5)P2. As calcium channel, it increases the pH in CC the lysosomal lumen, as sodium channel, it promotes lysosomal CC exocytosis (PubMed:32167471). Plays a crucial role in endolysosomal CC trafficking in the endolysosomal degradation pathway and is potentially CC involved in the homeostatic control of many macromolecules and cell CC metabolites (PubMed:25144390, PubMed:19387438, PubMed:20495006, CC PubMed:20547763, PubMed:23063126, PubMed:23394946, PubMed:32167471). CC Also expressed in melanosomes of pigmented cells where mediates a CC Ca(2+) channel and/or PI(3,5)P2-activated melanosomal Na(+) channel to CC acidify pH and inhibit tyrosinase activity required for melanogenesis CC and pigmentation (PubMed:27231233). Unlike the voltage-dependent TPCN1, CC TPCN2 is voltage independent and can be activated solely by PI(3,5)P2 CC binding. In contrast, PI(4,5)P2, PI(3,4)P2, PI(3)P and PI(5)P have no CC obvious effect on channel activation (By similarity). CC {ECO:0000250|UniProtKB:Q8NHX9, ECO:0000269|PubMed:19387438, CC ECO:0000269|PubMed:20495006, ECO:0000269|PubMed:20547763, CC ECO:0000269|PubMed:23063126, ECO:0000269|PubMed:23394946, CC ECO:0000269|PubMed:25144390, ECO:0000269|PubMed:27231233, CC ECO:0000269|PubMed:32167471}. CC -!- FUNCTION: (Microbial infection) During Ebola virus (EBOV) infection, CC controls the movement of endosomes containing virus particles and is CC required by EBOV to escape from the endosomal network into the cell CC cytoplasm. {ECO:0000269|PubMed:25722412}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Ca(2+)(in) = Ca(2+)(out); Xref=Rhea:RHEA:29671, CC ChEBI:CHEBI:29108; Evidence={ECO:0000269|PubMed:25144390}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:29673; CC Evidence={ECO:0000269|PubMed:25144390}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Na(+)(in) = Na(+)(out); Xref=Rhea:RHEA:34963, CC ChEBI:CHEBI:29101; Evidence={ECO:0000269|PubMed:27231233}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:34965; CC Evidence={ECO:0000250|UniProtKB:Q8NHX9}; CC -!- ACTIVITY REGULATION: Regulated by Mg(2+) ions, cytosolic Mg(2+) CC selectively inhibits outward current while lysosomal Mg(2+) modestly CC inhibits both the outward and inward currents. In the absence of CC Mg(2+), NAADP readily activates TPCN2, with properties similar to CC PI(3,5)P2 (By similarity). Na(+) current is inhibited by ATP in a CC MTORC-dependent manner. ATP sensitivity is independent of PI(3,5)P2 CC (PubMed:23394946). Both current elicited by PI(3,5)P2 as well as NAADP CC are inhibited by tetrandrine. {ECO:0000250|UniProtKB:Q8NHX9, CC ECO:0000269|PubMed:23394946, ECO:0000269|PubMed:25722412}. CC -!- SUBUNIT: Homodimer (Probable). Interacts with LRRK2. Interacts with CC HAX1. Interacts with MTOR; the interaction is required for TPCN2 ATP CC sensitivity (By similarity). Found in a complex with LSM12, TPCN1 and CC TPCN2 (By similarity). Interacts with LSM12 (By similarity). CC {ECO:0000250|UniProtKB:Q8NHX9, ECO:0000305|PubMed:19557428}. CC -!- SUBCELLULAR LOCATION: Late endosome membrane CC {ECO:0000305|PubMed:25144390}; Multi-pass membrane protein CC {ECO:0000255}. Lysosome membrane {ECO:0000269|PubMed:19557428, CC ECO:0000269|PubMed:20495006, ECO:0000269|PubMed:25144390, CC ECO:0000269|PubMed:32167471}; Multi-pass membrane protein CC {ECO:0000269|PubMed:19557428, ECO:0000269|PubMed:20495006}. Melanosome CC membrane {ECO:0000269|PubMed:27231233}; Multi-pass membrane protein CC {ECO:0000255}. Note=Only the acidic lysosomal fraction is sensitive to CC NAADP. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q8BWC0-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8BWC0-2; Sequence=VSP_023009, VSP_023010; CC Name=3; CC IsoId=Q8BWC0-3; Sequence=VSP_023008; CC -!- TISSUE SPECIFICITY: Widely expressed. Highly expressed in macrophages CC (PubMed:32167471). Expressed in pigmented cells (PubMed:27231233). CC {ECO:0000269|PubMed:19557428, ECO:0000269|PubMed:27231233, CC ECO:0000269|PubMed:32167471}. CC -!- DOMAIN: Each of the two internal repeats contains five hydrophobic CC transmembrane segments (S1, S2, S3, S5, S6) and one positively charged CC transmembrane segment (S4). S4 segments probably represent the voltage- CC sensor and are characterized by a series of positively charged amino CC acids at every third position (By similarity). {ECO:0000250}. CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:19557428}. CC -!- DISRUPTION PHENOTYPE: Loss of NAADP-mediated calcium release CC (PubMed:19387438). Mutant mice are highly susceptible to hepatic CC cholesterol overload, have hyperlipoproteinaemia and liver damage CC consistent with non-alcoholic fatty liver hepatitis (PubMed:25144390). CC TPCN1 and TPCN2 double knockouts are viable, fertile, have no obvious CC morphological abnormalities, and no obvious behavioral defects. After CC fasting for 3 days, they are less active and endurance performance is CC reduced by 8.3 fold in contrast to wild-type littermates that show no CC changes. Two days after re-introduction of food, mutants regain CC endurance and become as active as before fasting (PubMed:23394946). CC {ECO:0000269|PubMed:19387438, ECO:0000269|PubMed:23394946, CC ECO:0000269|PubMed:25144390}. CC -!- SIMILARITY: Belongs to the calcium channel alpha-1 subunit CC (TC 1.A.1.11) family. Two pore calcium channel subfamily. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAC41072.1; Type=Frameshift; Evidence={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; AK052930; BAC35207.1; -; mRNA. DR EMBL; AK090059; BAC41072.1; ALT_FRAME; mRNA. DR EMBL; BC025890; AAH25890.1; -; mRNA. DR EMBL; BC069857; AAH69857.1; -; mRNA. DR CCDS; CCDS40203.1; -. [Q8BWC0-1] DR RefSeq; NP_666318.2; NM_146206.5. [Q8BWC0-1] DR AlphaFoldDB; Q8BWC0; -. DR SMR; Q8BWC0; -. DR BioGRID; 231481; 1. DR STRING; 10090.ENSMUSP00000061308; -. DR GlyCosmos; Q8BWC0; 2 sites, No reported glycans. DR GlyGen; Q8BWC0; 3 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q8BWC0; -. DR PhosphoSitePlus; Q8BWC0; -. DR MaxQB; Q8BWC0; -. DR PaxDb; 10090-ENSMUSP00000061308; -. DR ProteomicsDB; 258825; -. [Q8BWC0-1] DR ProteomicsDB; 258826; -. [Q8BWC0-2] DR ProteomicsDB; 258827; -. [Q8BWC0-3] DR Pumba; Q8BWC0; -. DR DNASU; 233979; -. DR Ensembl; ENSMUST00000058022.6; ENSMUSP00000061308.5; ENSMUSG00000048677.10. [Q8BWC0-1] DR GeneID; 233979; -. DR KEGG; mmu:233979; -. DR UCSC; uc009kqw.1; mouse. [Q8BWC0-2] DR UCSC; uc009kqx.1; mouse. [Q8BWC0-1] DR AGR; MGI:2385297; -. DR CTD; 219931; -. DR MGI; MGI:2385297; Tpcn2. DR VEuPathDB; HostDB:ENSMUSG00000048677; -. DR eggNOG; KOG2301; Eukaryota. DR GeneTree; ENSGT00940000159763; -. DR HOGENOM; CLU_019500_1_0_1; -. DR InParanoid; Q8BWC0; -. DR OMA; FTESIEM; -. DR OrthoDB; 5403296at2759; -. DR PhylomeDB; Q8BWC0; -. DR TreeFam; TF328550; -. DR Reactome; R-MMU-2672351; Stimuli-sensing channels. DR BioGRID-ORCS; 233979; 2 hits in 78 CRISPR screens. DR PRO; PR:Q8BWC0; -. DR Proteomes; UP000000589; Chromosome 7. DR RNAct; Q8BWC0; Protein. DR Bgee; ENSMUSG00000048677; Expressed in granulocyte and 104 other cell types or tissues. DR ExpressionAtlas; Q8BWC0; baseline and differential. DR GO; GO:0005829; C:cytosol; IEA:GOC. DR GO; GO:0036020; C:endolysosome membrane; ISS:UniProtKB. DR GO; GO:0010008; C:endosome membrane; ISO:MGI. DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0033162; C:melanosome membrane; IDA:UniProtKB. DR GO; GO:0034702; C:monoatomic ion channel complex; IEA:UniProtKB-KW. DR GO; GO:0005262; F:calcium channel activity; ISO:MGI. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0097682; F:intracellular phosphatidylinositol-3,5-bisphosphate-sensitive monatomic cation channel activity; ISS:UniProtKB. DR GO; GO:0015280; F:ligand-gated sodium channel activity; IDA:UniProtKB. DR GO; GO:0072345; F:NAADP-sensitive calcium-release channel activity; IDA:UniProtKB. DR GO; GO:0080025; F:phosphatidylinositol-3,5-bisphosphate binding; ISS:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; ISO:MGI. DR GO; GO:0005245; F:voltage-gated calcium channel activity; IMP:UniProtKB. DR GO; GO:0019722; P:calcium-mediated signaling; IMP:UniProtKB. DR GO; GO:0075509; P:endocytosis involved in viral entry into host cell; IMP:UniProtKB. DR GO; GO:0090117; P:endosome to lysosome transport of low-density lipoprotein particle; IMP:UniProtKB. DR GO; GO:0006874; P:intracellular calcium ion homeostasis; ISO:MGI. DR GO; GO:0051452; P:intracellular pH reduction; IDA:UniProtKB. DR GO; GO:0007040; P:lysosome organization; ISO:MGI. DR GO; GO:0048086; P:negative regulation of developmental pigmentation; IDA:UniProtKB. DR GO; GO:0019065; P:receptor-mediated endocytosis of virus by host cell; ISO:MGI. DR GO; GO:0010506; P:regulation of autophagy; ISO:MGI. DR GO; GO:0017157; P:regulation of exocytosis; IMP:UniProtKB. DR GO; GO:0051209; P:release of sequestered calcium ion into cytosol; IMP:UniProtKB. DR GO; GO:0033280; P:response to vitamin D; IEA:Ensembl. DR GO; GO:0006939; P:smooth muscle contraction; IMP:UniProtKB. DR GO; GO:0035725; P:sodium ion transmembrane transport; ISS:UniProtKB. DR Gene3D; 1.10.287.70; -; 2. DR Gene3D; 1.20.120.350; Voltage-gated potassium channels. Chain C; 2. DR InterPro; IPR005821; Ion_trans_dom. DR InterPro; IPR028798; TPC2. DR InterPro; IPR027359; Volt_channel_dom_sf. DR PANTHER; PTHR46768; TWO PORE CALCIUM CHANNEL PROTEIN 2; 1. DR PANTHER; PTHR46768:SF1; TWO PORE CHANNEL PROTEIN 2; 1. DR Pfam; PF00520; Ion_trans; 2. DR SUPFAM; SSF81324; Voltage-gated potassium channels; 2. DR Genevisible; Q8BWC0; MM. PE 1: Evidence at protein level; KW Alternative splicing; Calcium; Calcium channel; Calcium transport; KW Endosome; Glycoprotein; Ion channel; Ion transport; Lysosome; Membrane; KW Reference proteome; Repeat; Transmembrane; Transmembrane helix; Transport; KW Voltage-gated channel. FT CHAIN 1..731 FT /note="Two pore channel protein 2" FT /id="PRO_0000276857" FT TOPO_DOM 1..68 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 69..89 FT /note="Helical; Name=S1 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 90..111 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 112..132 FT /note="Helical; Name=S2 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 133..139 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 140..160 FT /note="Helical; Name=S3 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 161..167 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 168..188 FT /note="Helical; Name=S4 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 189..203 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 204..224 FT /note="Helical; Name=S5 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 225..238 FT /note="Extracellular" FT /evidence="ECO:0000255" FT INTRAMEM 239..263 FT /note="Helical; Pore-forming" FT /evidence="ECO:0000255" FT TOPO_DOM 264..270 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 271..291 FT /note="Helical; Name=S6 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 292..417 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 418..438 FT /note="Helical; Name=S1 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 439..449 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 450..470 FT /note="Helical; Name=S2 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 471..486 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 487..507 FT /note="Helical; Name=S3 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 508..524 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 525..542 FT /note="Helical; Name=S4 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 543..564 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 565..585 FT /note="Helical; Name=S5 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 586..618 FT /note="Extracellular" FT /evidence="ECO:0000255" FT INTRAMEM 619..641 FT /note="Helical; Pore-forming" FT /evidence="ECO:0000255" FT TOPO_DOM 642..656 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 657..677 FT /note="Helical; Name=S6 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 678..731 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 187..191 FT /note="Interaction with phosphatidylinositol 3,5- FT bisphosphate" FT /evidence="ECO:0000250|UniProtKB:Q8NHX9" FT CARBOHYD 594 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19557428" FT CARBOHYD 601 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19557428" FT VAR_SEQ 1..526 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_023008" FT VAR_SEQ 1..453 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_023009" FT VAR_SEQ 454..514 FT /note="GILDYIFILYYLLELLFKVFALGLPGYLSYHSNVFDGLLTIILLVSEICTLA FT VYRLPHSGW -> MAAWDLGVSYGWAQPPLLLGAFSAWCPYSDYCCLFTPAASSPHPSA FT PPDFLTCLLCLPR (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_023010" FT MUTAGEN 257 FT /note="N->A: Complete loss of selectivity for calcium over FT monocovalent cations." FT /evidence="ECO:0000269|PubMed:20495006" FT MUTAGEN 594 FT /note="N->A: Loss of N-glycosylation; when associated with FT N-601." FT /evidence="ECO:0000269|PubMed:19557428" FT MUTAGEN 601 FT /note="N->A: Loss of N-glycosylation; when associated with FT N-594." FT /evidence="ECO:0000269|PubMed:19557428" FT MUTAGEN 643 FT /note="E->A: Partial loss of selectivity for calcium over FT monocovalent cations." FT /evidence="ECO:0000269|PubMed:20495006" FT CONFLICT 127 FT /note="K -> E (in Ref. 1; BAC41072)" FT /evidence="ECO:0000305" FT CONFLICT 224 FT /note="I -> V (in Ref. 1; BAC41072)" FT /evidence="ECO:0000305" FT CONFLICT 272 FT /note="F -> L (in Ref. 1; BAC41072)" FT /evidence="ECO:0000305" SQ SEQUENCE 731 AA; 83595 MW; 3C76487441344AD7 CRC64; MAAEEQPLLG RDRGSGQVHS GAAADQELCI DQAVVFIEDA IKYRSIYHRM DAGSLWLYRW YYSNVCQRVL GFIIFLILIL AFVEVPSSFT KTADVRYRSQ PWQPPCGLTE TIEAFCLLAF LVDLSVKGYL VGQAQLQQNL WLLAYFMVLV VSVVDWIVSL SLACEEPLRM RRLLRPFFLL QNSSMMKKTL KCIRWSLPEM ASVGLLLAIH LCLFTIIGML LFTIGEKDEA QDQERLAYFR NLPEALTSLL VLLTTSNNPD VMIPAYTQNR AFALFFIVFT LIGSLFLMNL LTAIIYNQFR GYLMKSLQTS LFRRRLGARA AYEVLASRAG PAGTTPELVG VNPETFLPVL QKTQLNKTHK QAIMQKVQSY EGRPMLADEF QKLFDEVDKG LAKERPLKPQ YQSPFLQTAQ FIFSHHYFDY LGNLVALGNL LSICVFLVLD SDLLPGERDD FVLGILDYIF ILYYLLELLF KVFALGLPGY LSYHSNVFDG LLTIILLVSE ICTLAVYRLP HSGWKPEQYG PLSLWDMTRL MNTLIVFRFL RIIPNIKPMA EVANTILGLI PNLRAFGGIL VVAYYVFAMI GINLFRGVIV PPGNSSLVPD NNSAVCGSFE QLGYWPNNFD DFAAALITLW NVMVVNNWQV ILEAYKRYAG PWSMVYFVLW WLVSSVIWIN LFLALLLENF LHRWDPQGHK QLLVGTKQMS VELMFRDILE EPKEEELMEK LHKHPHLHLC R //