TPC2_HUMAN
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 03-AUG-2022, entry version 162.
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, 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 [15]
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 [16]
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 [17]
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 [18]
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 [19]
RP SUBUNIT, AND INTERACTION WITH TPCN2.
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 [20] {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 [21]
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:30860481, PubMed:32167471, PubMed:31825310, PubMed:23063126,
CC PubMed:24776928, PubMed:23394946, PubMed:24502975). 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:32167471, PubMed:23394946, PubMed:18488028) (Probable). Ion
CC selectivity is not fixed but rather agonist-dependent and under defined
CC ionic conditions, can be readily activated by both NAADP and PI(3,5)P2
CC (PubMed:31825310, PubMed:32167471, PubMed:24502975). 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 Unlike the voltage-dependent TPCN1, TPCN2 is voltage independent and
CC can be activated solely by PI(3,5)P2 binding. In contrast, PI(4,5)P2,
CC PI(3,4)P2, PI(3)P and PI(5)P have no obvious effect on channel
CC activation (PubMed:30860481). {ECO:0000250|UniProtKB:Q8BWC0,
CC ECO:0000269|PubMed:18488028, ECO:0000269|PubMed:19387438,
CC ECO:0000269|PubMed:19620632, ECO:0000269|PubMed:20880839,
CC 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, ECO:0000305|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: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}.
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 PDBsum; 6NQ0; -.
DR PDBsum; 6NQ1; -.
DR PDBsum; 6NQ2; -.
DR AlphaFoldDB; Q8NHX9; -.
DR SMR; Q8NHX9; -.
DR BioGRID; 128596; 77.
DR IntAct; Q8NHX9; 55.
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 GlyGen; Q8NHX9; 2 sites.
DR iPTMnet; Q8NHX9; -.
DR PhosphoSitePlus; Q8NHX9; -.
DR BioMuta; TPCN2; -.
DR DMDM; 125991221; -.
DR EPD; Q8NHX9; -.
DR jPOST; Q8NHX9; -.
DR MassIVE; Q8NHX9; -.
DR MaxQB; Q8NHX9; -.
DR PaxDb; Q8NHX9; -.
DR PeptideAtlas; Q8NHX9; -.
DR PRIDE; Q8NHX9; -.
DR ProteomicsDB; 73782; -.
DR Antibodypedia; 16750; 80 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 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; 761764at2759; -.
DR PhylomeDB; Q8NHX9; -.
DR TreeFam; TF328550; -.
DR PathwayCommons; Q8NHX9; -.
DR Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR SignaLink; Q8NHX9; -.
DR BioGRID-ORCS; 219931; 5 hits in 1077 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 168 other tissues.
DR ExpressionAtlas; Q8NHX9; baseline and differential.
DR Genevisible; Q8NHX9; HS.
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:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:0042802; F:identical protein binding; IDA:UniProtKB.
DR GO; GO:0097682; F:intracellular phosphatidylinositol-3,5-bisphosphate-sensitive 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:0006874; P:cellular calcium ion homeostasis; IDA: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; ISS:UniProtKB.
DR GO; GO:0034220; P:ion transmembrane transport; TAS:Reactome.
DR GO; GO:0007040; P:lysosome organization; IGI:ParkinsonsUK-UCL.
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:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
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; 1.20.120.350; -; 2.
DR InterPro; IPR005821; Ion_trans_dom.
DR InterPro; IPR028798; TPC2.
DR InterPro; IPR027359; Volt_channel_dom_sf.
DR PANTHER; PTHR46768; PTHR46768; 1.
DR Pfam; PF00520; Ion_trans; 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
