ID TPC2_HUMAN Reviewed; 752 AA. AC Q8NHX9; Q9NT82; DT 06-FEB-2007, integrated into UniProtKB/Swiss-Prot. DT 06-FEB-2007, sequence version 2. DT 24-JUL-2024, entry version 173. DE RecName: Full=Two pore channel protein 2; DE AltName: Full=Two pore calcium channel protein 2; GN Name=TPCN2 {ECO:0000312|HGNC:HGNC:20820}; GN Synonyms=TPC2 {ECO:0000303|PubMed:25722412}; 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], FUNCTION, SUBCELLULAR LOCATION, TISSUE RP SPECIFICITY, VARIANTS PRO-564 AND GLU-734, AND CATALYTIC ACTIVITY. 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 [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS PRO-564 AND GLU-734. RC TISSUE=Blood; 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 382-752, AND VARIANTS PRO-564 AND RP GLU-734. RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [5] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=19620632; DOI=10.1083/jcb.200904073; RA Brailoiu E., Churamani D., Cai X., Schrlau M.G., Brailoiu G.C., Gao X., RA Hooper R., Boulware M.J., Dun N.J., Marchant J.S., Patel S.; RT "Essential requirement for two-pore channel 1 in NAADP-mediated calcium RT signaling."; RL J. Cell Biol. 186:201-209(2009). RN [6] RP FUNCTION, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF RP 11-LEU-LEU-12 AND LEU-265. RX PubMed=20880839; DOI=10.1074/jbc.m110.162073; RA Brailoiu E., Rahman T., Churamani D., Prole D.L., Brailoiu G.C., Hooper R., RA Taylor C.W., Patel S.; RT "An NAADP-gated two-pore channel targeted to the plasma membrane uncouples RT triggering from amplifying Ca2+ signals."; RL J. Biol. Chem. 285:38511-38516(2010). RN [7] RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-276, AND SUBCELLULAR RP LOCATION. 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 INTERACTION WITH LRRK2. RX PubMed=22012985; DOI=10.1093/hmg/ddr481; RA Gomez-Suaga P., Luzon-Toro B., Churamani D., Zhang L., Bloor-Young D., RA Patel S., Woodman P.G., Churchill G.C., Hilfiker S.; RT "Leucine-rich repeat kinase 2 regulates autophagy through a calcium- RT dependent pathway involving NAADP."; RL Hum. Mol. Genet. 21:511-525(2012). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH MTOR. 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 [10] RP INTERACTION WITH HAX1. RX PubMed=24188827; DOI=10.1016/j.febslet.2013.10.031; RA Lam A.K., Galione A., Lai F.A., Zissimopoulos S.; RT "Hax-1 identified as a two-pore channel (TPC)-binding protein."; RL FEBS Lett. 587:3782-3786(2013). RN [11] RP ACTIVITY REGULATION, FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF RP 11-LEU-LEU-12. RX PubMed=24502975; DOI=10.1002/embj.201387035; RA Jha A., Ahuja M., Patel S., Brailoiu E., Muallem S.; RT "Convergent regulation of the lysosomal two-pore channel-2 by Mg(2+), RT NAADP, PI(3,5)P(2) and multiple protein kinases."; RL EMBO J. 33:501-511(2014). RN [12] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=24776928; DOI=10.1038/nchembio.1522; RA Cang C., Bekele B., Ren D.; RT "The voltage-gated sodium channel TPC1 confers endolysosomal RT excitability."; RL Nat. Chem. Biol. 10:463-469(2014). RN [13] RP FUNCTION (MICROBIAL INFECTION), ACTIVITY REGULATION, SUBCELLULAR LOCATION, RP AND MUTAGENESIS OF LEU-265. 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 [14] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION. RX PubMed=27140606; DOI=10.1073/pnas.1600108113; RA Ambrosio A.L., Boyle J.A., Aradi A.E., Christian K.A., Di Pietro S.M.; RT "TPC2 controls pigmentation by regulating melanosome pH and size."; RL Proc. Natl. Acad. Sci. U.S.A. 113:5622-5627(2016). RN [15] RP FUNCTION, SUBCELLULAR LOCATION, AND CATALYTIC ACTIVITY. RX PubMed=31825310; DOI=10.7554/elife.51423; RA Zhang X., Chen W., Li P., Calvo R., Southall N., Hu X., Bryant-Genevier M., RA Feng X., Geng Q., Gao C., Yang M., Tang K., Ferrer M., Marugan J.J., Xu H.; RT "Agonist-specific voltage-dependent gating of lysosomal two-pore Na+ RT channels."; RL Elife 8:0-0(2019). RN [16] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP LYS-204 AND MET-484. 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). RN [17] RP FUNCTION (MICROBIAL INFECTION), AND ACTIVITY REGULATION. RX PubMed=32221306; DOI=10.1038/s41467-020-15562-9; RA Ou X., Liu Y., Lei X., Li P., Mi D., Ren L., Guo L., Guo R., Chen T., RA Hu J., Xiang Z., Mu Z., Chen X., Chen J., Hu K., Jin Q., Wang J., Qian Z.; RT "Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and RT its immune cross-reactivity with SARS-CoV."; RL Nat. Commun. 11:1620-1620(2020). RN [18] RP ERRATUM OF PUBMED:32221306. RX PubMed=33795662; DOI=10.1038/s41467-021-22614-1; RA Ou X., Liu Y., Lei X., Li P., Mi D., Ren L., Guo L., Guo R., Chen T., RA Hu J., Xiang Z., Mu Z., Chen X., Chen J., Hu K., Jin Q., Wang J., Qian Z.; RT "Author Correction: Characterization of spike glycoprotein of SARS-CoV-2 on RT virus entry and its immune cross-reactivity with SARS-CoV."; RL Nat. Commun. 12:2144-2144(2021). RN [19] RP REVIEW OF FUNCTION. RX PubMed=32679067; DOI=10.1016/j.tips.2020.06.002; RA Jin X., Zhang Y., Alharbi A., Hanbashi A., Alhoshani A., Parrington J.; RT "Targeting Two-Pore Channels: Current Progress and Future Challenges."; RL Trends Pharmacol. Sci. 41:582-594(2020). RN [20] RP SUBUNIT, AND INTERACTION WITH LSM12. RX PubMed=34362892; DOI=10.1038/s41467-021-24735-z; RA Zhang J., Guan X., Shah K., Yan J.; RT "Lsm12 is an NAADP receptor and a two-pore channel regulatory protein RT required for calcium mobilization from acidic organelles."; RL Nat. Commun. 12:4739-4739(2021). RN [21] {ECO:0007744|PDB:6NQ0, ECO:0007744|PDB:6NQ1, ECO:0007744|PDB:6NQ2} RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS) IN COMPLEX WITH RP PHOSPHATIDYLINOSITOL 3,5-BISPHOSPHATE, SUBUNIT, MUTAGENESIS OF LYS-203; RP LYS-204; LYS-207; SER-322; ARG-329 AND ILE-551, AND CATALYTIC ACTIVITY. RX PubMed=30860481; DOI=10.7554/elife.45222; RA She J., Zeng W., Guo J., Chen Q., Bai X.C., Jiang Y.; RT "Structural mechanisms of phospholipid activation of the human TPC2 RT channel."; RL Elife 8:0-0(2019). RN [22] RP VARIANTS LEU-484 AND GLU-734, AND ASSOCIATION WITH SHEP10. RX PubMed=18488028; DOI=10.1038/ng.160; RA Sulem P., Gudbjartsson D.F., Stacey S.N., Helgason A., Rafnar T., RA Jakobsdottir M., Steinberg S., Gudjonsson S.A., Palsson A., RA Thorleifsson G., Palsson S., Sigurgeirsson B., Thorisdottir K., RA Ragnarsson R., Benediktsdottir K.R., Aben K.K., Vermeulen S.H., RA Goldstein A.M., Tucker M.A., Kiemeney L.A., Olafsson J.H., Gulcher J., RA Kong A., Thorsteinsdottir U., Stefansson K.; RT "Two newly identified genetic determinants of pigmentation in Europeans."; RL Nat. Genet. 40:835-837(2008). 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:19620632, PubMed:20880839, CC PubMed:23063126, PubMed:23394946, PubMed:24502975, PubMed:24776928, CC PubMed:30860481, PubMed:31825310, PubMed:32167471). Localizes to the CC lysosomal and late endosome membranes where it regulates organellar CC membrane excitability, membrane trafficking, and pH homeostasis. Is CC associated with a plethora of physiological processes, including mTOR- CC dependent nutrient sensing, skin pigmentation and autophagy CC (PubMed:18488028, PubMed:23394946, PubMed:32167471). Ion selectivity is CC not fixed but rather agonist-dependent and under defined ionic CC conditions, can be readily activated by both NAADP and PI(3,5)P2 CC (PubMed:24502975, PubMed:31825310, PubMed:32167471). As calcium CC channel, it increases the pH in the lysosomal lumen, as sodium channel, CC it promotes lysosomal exocytosis (PubMed:31825310, PubMed:32167471). CC Plays a crucial role in endolysosomal trafficking in the endolysosomal CC degradation pathway and is potentially involved in the homeostatic CC control of many macromolecules and cell metabolites (By similarity) CC (PubMed:18488028, PubMed:19387438, PubMed:19620632, PubMed:20880839, CC PubMed:23063126, PubMed:23394946, PubMed:24502975, PubMed:24776928, CC PubMed:31825310, PubMed:32167471, PubMed:32679067). Also expressed in CC melanosomes of pigmented cells where mediates a Ca(2+) channel and/or CC PI(3,5)P2-activated melanosomal Na(+) channel to acidify pH and inhibit CC tyrosinase activity required for melanogenesis and pigmentation CC (PubMed:27140606). Unlike the voltage-dependent TPCN1, TPCN2 is voltage CC independent and can be activated solely by PI(3,5)P2 binding. In CC contrast, PI(4,5)P2, PI(3,4)P2, PI(3)P and PI(5)P have no obvious CC effect on channel activation (PubMed:30860481). CC {ECO:0000250|UniProtKB:Q8BWC0, ECO:0000269|PubMed:18488028, CC ECO:0000269|PubMed:19387438, ECO:0000269|PubMed:19620632, CC ECO:0000269|PubMed:20880839, ECO:0000269|PubMed:23063126, CC ECO:0000269|PubMed:23394946, ECO:0000269|PubMed:24502975, CC ECO:0000269|PubMed:24776928, ECO:0000269|PubMed:27140606, CC ECO:0000269|PubMed:30860481, ECO:0000269|PubMed:31825310, CC ECO:0000269|PubMed:32167471, ECO:0000269|PubMed:32679067}. 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 -!- FUNCTION: (Microbial infection) Required for cell entry of CC coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus EMC CC (HCoV-EMC), by endocytosis. {ECO:0000269|PubMed:32221306}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Na(+)(in) = Na(+)(out); Xref=Rhea:RHEA:34963, CC ChEBI:CHEBI:29101; Evidence={ECO:0000269|PubMed:23063126, CC ECO:0000269|PubMed:23394946, ECO:0000269|PubMed:24502975, CC ECO:0000269|PubMed:24776928, ECO:0000269|PubMed:30860481, CC ECO:0000269|PubMed:31825310, ECO:0000269|PubMed:32167471}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:34965; CC Evidence={ECO:0000269|PubMed:23063126, ECO:0000269|PubMed:23394946, CC ECO:0000269|PubMed:24502975, ECO:0000269|PubMed:24776928, CC ECO:0000269|PubMed:30860481, ECO:0000269|PubMed:31825310, CC ECO:0000269|PubMed:32167471}; CC -!- CATALYTIC ACTIVITY: CC Reaction=Ca(2+)(in) = Ca(2+)(out); Xref=Rhea:RHEA:29671, CC ChEBI:CHEBI:29108; Evidence={ECO:0000269|PubMed:19387438, CC ECO:0000269|PubMed:20880839, ECO:0000269|PubMed:24502975, CC ECO:0000269|PubMed:27140606, ECO:0000269|PubMed:32167471}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:29673; CC Evidence={ECO:0000269|PubMed:19387438, ECO:0000269|PubMed:20880839, CC ECO:0000269|PubMed:24502975, ECO:0000269|PubMed:32167471}; 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 (PubMed:24502975). 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:0000269|PubMed:23394946, CC ECO:0000269|PubMed:24502975, ECO:0000269|PubMed:25722412, CC ECO:0000269|PubMed:32221306}. CC -!- SUBUNIT: Homodimer (PubMed:30860481). Interacts with LRRK2 CC (PubMed:22012985). Interacts with HAX1 (PubMed:24188827). Interacts CC with MTOR; the interaction is required for TPCN2 ATP sensitivity CC (PubMed:23394946). Found in a complex with LSM12, TPCN1 and TPCN2 CC (PubMed:34362892). Interacts with LSM12 (PubMed:34362892). CC {ECO:0000269|PubMed:22012985, ECO:0000269|PubMed:23394946, CC ECO:0000269|PubMed:24188827, ECO:0000269|PubMed:30860481, CC ECO:0000269|PubMed:34362892}. CC -!- INTERACTION: CC Q8NHX9; O00165: HAX1; NbExp=4; IntAct=EBI-5239949, EBI-357001; CC Q8NHX9; P42345: MTOR; NbExp=2; IntAct=EBI-5239949, EBI-359260; CC Q8NHX9; Q9ULQ1: TPCN1; NbExp=9; IntAct=EBI-5239949, EBI-5239895; CC Q8NHX9; Q8NHX9: TPCN2; NbExp=4; IntAct=EBI-5239949, EBI-5239949; CC -!- SUBCELLULAR LOCATION: Late endosome membrane CC {ECO:0000269|PubMed:32167471}; Multi-pass membrane protein CC {ECO:0000255}. Lysosome membrane {ECO:0000269|PubMed:20880839, CC ECO:0000269|PubMed:23063126, ECO:0000269|PubMed:31825310, CC ECO:0000269|PubMed:32167471}; Multi-pass membrane protein CC {ECO:0000255}. Melanosome membrane {ECO:0000269|PubMed:27140606}; CC Multi-pass membrane protein {ECO:0000255}. CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed at high level in liver CC and kidney. {ECO:0000269|PubMed:19387438}. 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:0000250|UniProtKB:Q8BWC0}. CC -!- POLYMORPHISM: Genetic variants in TPCN2 define the skin/hair/eye CC pigmentation variation locus 10 (SHEP10) [MIM:612267]. Hair, eye and CC skin pigmentation are among the most visible examples of human CC phenotypic variation, with a broad normal range that is subject to CC substantial geographic stratification. In the case of skin, individuals CC tend to have lighter pigmentation with increasing distance from the CC equator. By contrast, the majority of variation in human eye and hair CC color is found among individuals of European ancestry, with most other CC human populations fixed for brown eyes and black hair. CC {ECO:0000269|PubMed:18488028}. CC -!- SIMILARITY: Belongs to the calcium channel alpha-1 subunit (TC CC 1.A.1.11) family. Two pore calcium channel 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; AY029200; AAK31802.1; -; mRNA. DR EMBL; AP003071; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC063008; AAH63008.1; -; mRNA. DR EMBL; AL137479; CAB70760.1; -; mRNA. DR CCDS; CCDS8189.1; -. DR PIR; T46421; T46421. DR RefSeq; NP_620714.2; NM_139075.3. DR PDB; 6NQ0; EM; 3.70 A; A/B=1-752. DR PDB; 6NQ1; EM; 3.50 A; A/B=1-752. DR PDB; 6NQ2; EM; 3.40 A; A/B=1-752. DR PDBsum; 6NQ0; -. DR PDBsum; 6NQ1; -. DR PDBsum; 6NQ2; -. DR AlphaFoldDB; Q8NHX9; -. DR EMDB; EMD-0477; -. DR EMDB; EMD-0478; -. DR EMDB; EMD-0479; -. DR SMR; Q8NHX9; -. DR BioGRID; 128596; 78. DR IntAct; Q8NHX9; 56. DR MINT; Q8NHX9; -. DR STRING; 9606.ENSP00000294309; -. DR DrugCentral; Q8NHX9; -. DR GuidetoPHARMACOLOGY; 393; -. DR TCDB; 1.A.1.11.19; the voltage-gated ion channel (vic) superfamily. DR GlyCosmos; Q8NHX9; 2 sites, No reported glycans. DR GlyGen; Q8NHX9; 2 sites. DR iPTMnet; Q8NHX9; -. DR PhosphoSitePlus; Q8NHX9; -. DR BioMuta; TPCN2; -. DR DMDM; 125991221; -. DR jPOST; Q8NHX9; -. DR MassIVE; Q8NHX9; -. DR PaxDb; 9606-ENSP00000294309; -. DR PeptideAtlas; Q8NHX9; -. DR ProteomicsDB; 73782; -. DR Pumba; Q8NHX9; -. DR Antibodypedia; 16750; 90 antibodies from 24 providers. DR DNASU; 219931; -. DR Ensembl; ENST00000294309.8; ENSP00000294309.3; ENSG00000162341.18. DR GeneID; 219931; -. DR KEGG; hsa:219931; -. DR MANE-Select; ENST00000294309.8; ENSP00000294309.3; NM_139075.4; NP_620714.2. DR UCSC; uc001oos.3; human. DR AGR; HGNC:20820; -. DR CTD; 219931; -. DR DisGeNET; 219931; -. DR GeneCards; TPCN2; -. DR HGNC; HGNC:20820; TPCN2. DR HPA; ENSG00000162341; Low tissue specificity. DR MalaCards; TPCN2; -. DR MIM; 612163; gene. DR MIM; 612267; phenotype. DR neXtProt; NX_Q8NHX9; -. DR OpenTargets; ENSG00000162341; -. DR PharmGKB; PA134937857; -. DR VEuPathDB; HostDB:ENSG00000162341; -. DR eggNOG; KOG2301; Eukaryota. DR GeneTree; ENSGT00940000159763; -. DR HOGENOM; CLU_019500_1_0_1; -. DR InParanoid; Q8NHX9; -. DR OMA; FTESIEM; -. DR OrthoDB; 5403296at2759; -. DR PhylomeDB; Q8NHX9; -. DR TreeFam; TF328550; -. DR PathwayCommons; Q8NHX9; -. DR Reactome; R-HSA-2672351; Stimuli-sensing channels. DR SignaLink; Q8NHX9; -. DR BioGRID-ORCS; 219931; 6 hits in 1158 CRISPR screens. DR ChiTaRS; TPCN2; human. DR GeneWiki; TPCN2; -. DR GenomeRNAi; 219931; -. DR Pharos; Q8NHX9; Tchem. DR PRO; PR:Q8NHX9; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q8NHX9; Protein. DR Bgee; ENSG00000162341; Expressed in pancreatic ductal cell and 170 other cell types or tissues. DR ExpressionAtlas; Q8NHX9; baseline and differential. DR GO; GO:0005829; C:cytosol; IEA:GOC. DR GO; GO:0036020; C:endolysosome membrane; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB. 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:ParkinsonsUK-UCL. 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; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB. DR GO; GO:0097682; F:intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity; IDA: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; IDA:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0005245; F:voltage-gated calcium channel activity; ISS:UniProtKB. DR GO; GO:0019722; P:calcium-mediated signaling; IGI:ParkinsonsUK-UCL. 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; ISS:UniProtKB. DR GO; GO:0006874; P:intracellular calcium ion homeostasis; IDA:UniProtKB. DR GO; GO:0051452; P:intracellular pH reduction; IDA:UniProtKB. DR GO; GO:0007040; P:lysosome organization; IGI:ParkinsonsUK-UCL. DR GO; GO:0034220; P:monoatomic ion transmembrane transport; TAS:Reactome. 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; IDA:UniProtKB. DR GO; GO:0010506; P:regulation of autophagy; IGI:ParkinsonsUK-UCL. DR GO; GO:0017157; P:regulation of exocytosis; ISS:UniProtKB. DR GO; GO:0051209; P:release of sequestered calcium ion into cytosol; IEA:Ensembl. DR GO; GO:0033280; P:response to vitamin D; IEA:Ensembl. DR GO; GO:0006939; P:smooth muscle contraction; ISS:UniProtKB. DR GO; GO:0035725; P:sodium ion transmembrane transport; IDA: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. PE 1: Evidence at protein level; KW 3D-structure; Calcium; Calcium channel; Calcium transport; Endosome; KW Glycoprotein; Ion channel; Ion transport; Lysosome; Membrane; KW Reference proteome; Repeat; Transmembrane; Transmembrane helix; Transport; KW Voltage-gated channel. FT CHAIN 1..752 FT /note="Two pore channel protein 2" FT /id="PRO_0000276856" FT TOPO_DOM 1..84 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 85..105 FT /note="Helical; Name=S1 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 106..127 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 128..148 FT /note="Helical; Name=S2 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 149..155 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 156..176 FT /note="Helical; Name=S3 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 177..183 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 184..204 FT /note="Helical; Name=S4 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 205..218 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 219..239 FT /note="Helical; Name=S5 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 240..254 FT /note="Extracellular" FT /evidence="ECO:0000255" FT INTRAMEM 255..279 FT /note="Helical; Pore-forming" FT /evidence="ECO:0000255" FT TOPO_DOM 280..289 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 290..310 FT /note="Helical; Name=S6 of repeat I" FT /evidence="ECO:0000255" FT TOPO_DOM 311..436 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 437..459 FT /note="Helical; Name=S1 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 460..465 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 466..486 FT /note="Helical; Name=S2 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 487..502 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 503..523 FT /note="Helical; Name=S3 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 524..554 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 555..575 FT /note="Helical; Name=S4 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 576..580 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 581..601 FT /note="Helical; Name=S5 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 602..635 FT /note="Extracellular" FT /evidence="ECO:0000255" FT INTRAMEM 636..658 FT /note="Helical; Pore-forming" FT /evidence="ECO:0000255" FT TOPO_DOM 659..673 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 674..694 FT /note="Helical; Name=S6 of repeat II" FT /evidence="ECO:0000255" FT TOPO_DOM 695..752 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 203..207 FT /note="Interaction with phosphatidylinositol 3,5- FT bisphosphate" FT /evidence="ECO:0000269|PubMed:30860481" FT CARBOHYD 611 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 618 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VARIANT 376 FT /note="K -> R (in dbSNP:rs3750965)" FT /id="VAR_030492" FT VARIANT 484 FT /note="M -> L (associated with SHEP10; dbSNP:rs35264875)" FT /evidence="ECO:0000269|PubMed:18488028" FT /id="VAR_047956" FT VARIANT 564 FT /note="L -> P (in dbSNP:rs2376558)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:17974005, ECO:0000269|PubMed:19387438" FT /id="VAR_030493" FT VARIANT 734 FT /note="G -> E (associated with SHEP10; dbSNP:rs3829241)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:17974005, ECO:0000269|PubMed:18488028, FT ECO:0000269|PubMed:19387438" FT /id="VAR_030494" FT MUTAGEN 11..12 FT /note="LL->AA: Localizes at the plasma membrane." FT /evidence="ECO:0000269|PubMed:20880839, FT ECO:0000269|PubMed:24502975" FT MUTAGEN 203 FT /note="K->A: Strongly reduces binding with FT phosphatidylinositol 3,5-bisphosphate." FT /evidence="ECO:0000269|PubMed:30860481" FT MUTAGEN 204 FT /note="K->A: Strongly reduces binding with FT phosphatidylinositol 3,5-bisphosphate. Decreases sodium FT transport. No effect on calcium release." FT /evidence="ECO:0000269|PubMed:30860481, FT ECO:0000269|PubMed:32167471" FT MUTAGEN 207 FT /note="K->A: Reduces binding with phosphatidylinositol 3,5- FT bisphosphate." FT /evidence="ECO:0000269|PubMed:30860481" FT MUTAGEN 265 FT /note="L->P: No effect on lysosomal location. Loss of FT NAADP-sensitive calcium-release channel activity. Inhibits FT Ebola virus infection." FT /evidence="ECO:0000269|PubMed:20880839, FT ECO:0000269|PubMed:25722412" FT MUTAGEN 276 FT /note="D->K: Not activated by phosphatidylinositol 3,5- FT bisphosphate." FT /evidence="ECO:0000269|PubMed:23063126" FT MUTAGEN 322 FT /note="S->A: Reduces binding with phosphatidylinositol 3,5- FT bisphosphate." FT /evidence="ECO:0000269|PubMed:30860481" FT MUTAGEN 329 FT /note="R->A: Reduces binding with phosphatidylinositol 3,5- FT bisphosphate." FT /evidence="ECO:0000269|PubMed:30860481" FT MUTAGEN 484 FT /note="M->L: Gain of function. Increased sodium currents." FT /evidence="ECO:0000269|PubMed:32167471" FT MUTAGEN 551 FT /note="I->R: Requires both phosphatidylinositol 3,5- FT bisphosphate and a positive membrane potential for FT activation." FT /evidence="ECO:0000269|PubMed:30860481" FT HELIX 40..57 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 70..77 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 80..95 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 96..98 FT /evidence="ECO:0007829|PDB:6NQ2" FT STRAND 99..102 FT /evidence="ECO:0007829|PDB:6NQ2" FT STRAND 111..113 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 124..145 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 149..154 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 156..177 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 186..188 FT /evidence="ECO:0007829|PDB:6NQ2" FT TURN 189..191 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 192..198 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 201..237 FT /evidence="ECO:0007829|PDB:6NQ2" FT STRAND 254..257 FT /evidence="ECO:0007829|PDB:6NQ1" FT HELIX 258..269 FT /evidence="ECO:0007829|PDB:6NQ2" FT TURN 274..278 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 279..284 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 286..288 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 289..298 FT /evidence="ECO:0007829|PDB:6NQ2" FT TURN 299..301 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 302..312 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 318..341 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 359..365 FT /evidence="ECO:0007829|PDB:6NQ2" FT STRAND 366..369 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 373..385 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 393..399 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 419..427 FT /evidence="ECO:0007829|PDB:6NQ2" FT TURN 428..431 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 434..458 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 469..488 FT /evidence="ECO:0007829|PDB:6NQ2" FT TURN 489..491 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 493..498 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 500..522 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 540..551 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 552..557 FT /evidence="ECO:0007829|PDB:6NQ2" FT TURN 558..560 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 566..576 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 580..600 FT /evidence="ECO:0007829|PDB:6NQ2" FT STRAND 601..603 FT /evidence="ECO:0007829|PDB:6NQ2" FT TURN 626..630 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 631..633 FT /evidence="ECO:0007829|PDB:6NQ1" FT HELIX 639..650 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 655..665 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 668..670 FT /evidence="ECO:0007829|PDB:6NQ1" FT HELIX 671..680 FT /evidence="ECO:0007829|PDB:6NQ2" FT TURN 681..683 FT /evidence="ECO:0007829|PDB:6NQ2" FT HELIX 684..697 FT /evidence="ECO:0007829|PDB:6NQ2" SQ SEQUENCE 752 AA; 85243 MW; 8A0794952A46C67E CRC64; MAEPQAESEP LLGGARGGGG DWPAGLTTYR SIQVGPGAAA RWDLCIDQAV VFIEDAIQYR SINHRVDASS MWLYRRYYSN VCQRTLSFTI FLILFLAFIE TPSSLTSTAD VRYRAAPWEP PCGLTESVEV LCLLVFAADL SVKGYLFGWA HFQKNLWLLG YLVVLVVSLV DWTVSLSLVC HEPLRIRRLL RPFFLLQNSS MMKKTLKCIR WSLPEMASVG LLLAIHLCLF TMFGMLLFAG GKQDDGQDRE RLTYFQNLPE SLTSLLVLLT TANNPDVMIP AYSKNRAYAI FFIVFTVIGS LFLMNLLTAI IYSQFRGYLM KSLQTSLFRR RLGTRAAFEV LSSMVGEGGA FPQAVGVKPQ NLLQVLQKVQ LDSSHKQAMM EKVRSYGSVL LSAEEFQKLF NELDRSVVKE HPPRPEYQSP FLQSAQFLFG HYYFDYLGNL IALANLVSIC VFLVLDADVL PAERDDFILG ILNCVFIVYY LLEMLLKVFA LGLRGYLSYP SNVFDGLLTV VLLVLEISTL AVYRLPHPGW RPEMVGLLSL WDMTRMLNML IVFRFLRIIP SMKLMAVVAS TVLGLVQNMR AFGGILVVVY YVFAIIGINL FRGVIVALPG NSSLAPANGS APCGSFEQLE YWANNFDDFA AALVTLWNLM VVNNWQVFLD AYRRYSGPWS KIYFVLWWLV SSVIWVNLFL ALILENFLHK WDPRSHLQPL AGTPEATYQM TVELLFRDIL EEPGEDELTE RLSQHPHLWL CR //