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   02-OCT-2024, entry version 174.
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}.
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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   PDB; 8OUO; EM; 3.00 A; A/B=1-752.
DR   PDBsum; 6NQ0; -.
DR   PDBsum; 6NQ1; -.
DR   PDBsum; 6NQ2; -.
DR   PDBsum; 8OUO; -.
DR   AlphaFoldDB; Q8NHX9; -.
DR   EMDB; EMD-0477; -.
DR   EMDB; EMD-0478; -.
DR   EMDB; EMD-0479; -.
DR   EMDB; EMD-17197; -.
DR   SMR; Q8NHX9; -.
DR   BioGRID; 128596; 78.
DR   IntAct; Q8NHX9; 62.
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; 89 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   Proteomics identification; Reference proteome; Repeat; Transmembrane;
KW   Transmembrane helix; Transport; 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
//