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Database: UniProt
Entry: TPC2_HUMAN
LinkDB: TPC2_HUMAN
Original site: 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   27-SEP-2017, entry version 129.
DE   RecName: Full=Two pore calcium channel protein 2;
DE   AltName: Full=Voltage-dependent calcium channel protein TPC2;
GN   Name=TPCN2; Synonyms=TPC2;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP   SPECIFICITY, AND VARIANTS PRO-564 AND GLU-734.
RX   PubMed=19387438; DOI=10.1038/nature08030;
RA   Calcraft P.J., Ruas M., Pan Z., Cheng X., Arredouani A., Hao X.,
RA   Tang J., Rietdorf K., Teboul L., Chuang K.T., Lin P., Xiao R.,
RA   Wang C., Zhu Y., Lin Y., Wyatt C.N., Parrington J., Ma J., Evans A.M.,
RA   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.,
RA   Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA   FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA   Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA   Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA   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
RP   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
RT   project: 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
RP   PRO-564 AND 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.,
RA   Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA   Ottenwaelder B., Poustka A., 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.,
RA   Gao X., Hooper R., Boulware M.J., Dun N.J., Marchant J.S., Patel S.;
RT   "Essential requirement for two-pore channel 1 in NAADP-mediated
RT   calcium signaling.";
RL   J. Cell Biol. 186:201-209(2009).
RN   [6]
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   [7]
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   [8]
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
RT   Europeans.";
RL   Nat. Genet. 40:835-837(2008).
CC   -!- FUNCTION: Nicotinic acid adenine dinucleotide phosphate (NAADP)
CC       receptor that may function as one of the major voltage-gated
CC       Ca(2+) channels (VDCC) across the lysosomal membrane. May be
CC       involved in smooth muscle contraction.
CC       {ECO:0000269|PubMed:19387438, ECO:0000269|PubMed:19620632}.
CC   -!- SUBUNIT: Homodimer (By similarity). Interacts with LRRK2
CC       (PubMed:22012985). Interacts with HAX1 (PubMed:24188827).
CC       {ECO:0000250|UniProtKB:Q8BWC0, ECO:0000269|PubMed:22012985,
CC       ECO:0000269|PubMed:24188827}.
CC   -!- INTERACTION:
CC       Self; NbExp=4; IntAct=EBI-5239949, EBI-5239949;
CC       O00165:HAX1; NbExp=4; IntAct=EBI-5239949, EBI-357001;
CC       P42345:MTOR; NbExp=2; IntAct=EBI-5239949, EBI-359260;
CC       Q9ULQ1:TPCN1; NbExp=9; IntAct=EBI-5239949, EBI-5239895;
CC   -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000250}; Multi-pass
CC       membrane protein {ECO:0000250}. Note=Only the acidic lysosomal
CC       fraction is sensitive to NAADP. {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Widely expressed. Expressed at high level in
CC       liver 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
CC       charged transmembrane segment (S4). S4 segments probably represent
CC       the voltage-sensor and are characterized by a series of positively
CC       charged amino acids at every third position (By similarity).
CC       {ECO:0000250}.
CC   -!- PTM: N-glycosylated. {ECO:0000250}.
CC   -!- POLYMORPHISM: Genetic variants in TPCN2 define the skin/hair/eye
CC       pigmentation variation locus 10 (SHEP10) [MIM:612267]. Hair, eye
CC       and 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,
CC       individuals tend to have lighter pigmentation with increasing
CC       distance from the equator. By contrast, the majority of variation
CC       in human eye and hair color is found among individuals of European
CC       ancestry, with most other human populations fixed for brown eyes
CC       and black hair. {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.
CC       {ECO:0000305}.
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   UniGene; Hs.131851; -.
DR   ProteinModelPortal; Q8NHX9; -.
DR   BioGrid; 128596; 59.
DR   IntAct; Q8NHX9; 3.
DR   STRING; 9606.ENSP00000294309; -.
DR   GuidetoPHARMACOLOGY; 393; -.
DR   TCDB; 1.A.1.11.19; the voltage-gated ion channel (vic) superfamily.
DR   iPTMnet; Q8NHX9; -.
DR   PhosphoSitePlus; Q8NHX9; -.
DR   BioMuta; TPCN2; -.
DR   DMDM; 125991221; -.
DR   EPD; Q8NHX9; -.
DR   MaxQB; Q8NHX9; -.
DR   PaxDb; Q8NHX9; -.
DR   PeptideAtlas; Q8NHX9; -.
DR   PRIDE; Q8NHX9; -.
DR   Ensembl; ENST00000294309; ENSP00000294309; ENSG00000162341.
DR   GeneID; 219931; -.
DR   KEGG; hsa:219931; -.
DR   UCSC; uc001oos.3; human.
DR   CTD; 219931; -.
DR   DisGeNET; 219931; -.
DR   EuPathDB; HostDB:ENSG00000162341.15; -.
DR   GeneCards; TPCN2; -.
DR   H-InvDB; HIX0019754; -.
DR   HGNC; HGNC:20820; TPCN2.
DR   HPA; HPA016561; -.
DR   HPA; HPA027080; -.
DR   MIM; 612163; gene.
DR   MIM; 612267; phenotype.
DR   neXtProt; NX_Q8NHX9; -.
DR   OpenTargets; ENSG00000162341; -.
DR   PharmGKB; PA134937857; -.
DR   eggNOG; ENOG410INF1; Eukaryota.
DR   eggNOG; ENOG4111V21; LUCA.
DR   GeneTree; ENSGT00530000063660; -.
DR   HOGENOM; HOG000154668; -.
DR   HOVERGEN; HBG079776; -.
DR   InParanoid; Q8NHX9; -.
DR   KO; K14077; -.
DR   OMA; SSVIWVN; -.
DR   OrthoDB; EOG091G045K; -.
DR   PhylomeDB; Q8NHX9; -.
DR   TreeFam; TF328550; -.
DR   Reactome; R-HSA-2672351; Stimuli-sensing channels.
DR   ChiTaRS; TPCN2; human.
DR   GeneWiki; TPCN2; -.
DR   GenomeRNAi; 219931; -.
DR   PRO; PR:Q8NHX9; -.
DR   Proteomes; UP000005640; Chromosome 11.
DR   Bgee; ENSG00000162341; -.
DR   CleanEx; HS_TPCN2; -.
DR   ExpressionAtlas; Q8NHX9; baseline and differential.
DR   Genevisible; Q8NHX9; HS.
DR   GO; GO:0010008; C:endosome membrane; IDA:UniProtKB.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR   GO; GO:0005764; C:lysosome; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0072345; F:NAADP-sensitive calcium-release channel activity; 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:0034220; P:ion transmembrane transport; TAS:Reactome.
DR   GO; GO:0007040; P:lysosome organization; IGI:ParkinsonsUK-UCL.
DR   GO; GO:0086010; P:membrane depolarization during action potential; IBA:GO_Central.
DR   GO; GO:0010506; P:regulation of autophagy; IGI:ParkinsonsUK-UCL.
DR   GO; GO:0033280; P:response to vitamin D; IEA:Ensembl.
DR   GO; GO:0006939; P:smooth muscle contraction; ISS:UniProtKB.
DR   InterPro; IPR005821; Ion_trans_dom.
DR   InterPro; IPR028798; TPC2.
DR   PANTHER; PTHR10037:SF270; PTHR10037:SF270; 1.
DR   Pfam; PF00520; Ion_trans; 2.
PE   1: Evidence at protein level;
KW   Calcium; Calcium channel; Calcium transport; Complete proteome;
KW   Glycoprotein; Ion channel; Ion transport; Lysosome; Membrane;
KW   Polymorphism; Reference proteome; Repeat; Transmembrane;
KW   Transmembrane helix; Transport; Voltage-gated channel.
FT   CHAIN         1    752       Two pore calcium channel protein 2.
FT                                /FTId=PRO_0000276856.
FT   TOPO_DOM      1     84       Cytoplasmic. {ECO:0000255}.
FT   TRANSMEM     85    105       Helical; Name=S1 of repeat I.
FT                                {ECO:0000255}.
FT   TOPO_DOM    106    127       Extracellular. {ECO:0000255}.
FT   TRANSMEM    128    148       Helical; Name=S2 of repeat I.
FT                                {ECO:0000255}.
FT   TOPO_DOM    149    155       Cytoplasmic. {ECO:0000255}.
FT   TRANSMEM    156    176       Helical; Name=S3 of repeat I.
FT                                {ECO:0000255}.
FT   TOPO_DOM    177    183       Extracellular. {ECO:0000255}.
FT   TRANSMEM    184    204       Helical; Name=S4 of repeat I.
FT                                {ECO:0000255}.
FT   TOPO_DOM    205    218       Cytoplasmic. {ECO:0000255}.
FT   TRANSMEM    219    239       Helical; Name=S5 of repeat I.
FT                                {ECO:0000255}.
FT   TOPO_DOM    240    254       Extracellular. {ECO:0000255}.
FT   INTRAMEM    255    279       Helical; Pore-forming. {ECO:0000255}.
FT   TOPO_DOM    280    289       Extracellular. {ECO:0000255}.
FT   TRANSMEM    290    310       Helical; Name=S6 of repeat I.
FT                                {ECO:0000255}.
FT   TOPO_DOM    311    436       Cytoplasmic. {ECO:0000255}.
FT   TRANSMEM    437    459       Helical; Name=S1 of repeat II.
FT                                {ECO:0000255}.
FT   TOPO_DOM    460    465       Extracellular. {ECO:0000255}.
FT   TRANSMEM    466    486       Helical; Name=S2 of repeat II.
FT                                {ECO:0000255}.
FT   TOPO_DOM    487    502       Cytoplasmic. {ECO:0000255}.
FT   TRANSMEM    503    523       Helical; Name=S3 of repeat II.
FT                                {ECO:0000255}.
FT   TOPO_DOM    524    554       Extracellular. {ECO:0000255}.
FT   TRANSMEM    555    575       Helical; Name=S4 of repeat II.
FT                                {ECO:0000255}.
FT   TOPO_DOM    576    580       Cytoplasmic. {ECO:0000255}.
FT   TRANSMEM    581    601       Helical; Name=S5 of repeat II.
FT                                {ECO:0000255}.
FT   TOPO_DOM    602    635       Extracellular. {ECO:0000255}.
FT   INTRAMEM    636    658       Helical; Pore-forming. {ECO:0000255}.
FT   TOPO_DOM    659    673       Extracellular. {ECO:0000255}.
FT   TRANSMEM    674    694       Helical; Name=S6 of repeat II.
FT                                {ECO:0000255}.
FT   TOPO_DOM    695    752       Cytoplasmic. {ECO:0000255}.
FT   COMPBIAS     17     20       Poly-Gly.
FT   CARBOHYD    611    611       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    618    618       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   VARIANT     376    376       K -> R (in dbSNP:rs3750965).
FT                                /FTId=VAR_030492.
FT   VARIANT     484    484       M -> L (associated with SHEP10;
FT                                dbSNP:rs35264875).
FT                                {ECO:0000269|PubMed:18488028}.
FT                                /FTId=VAR_047956.
FT   VARIANT     564    564       L -> P (in dbSNP:rs2376558).
FT                                {ECO:0000269|PubMed:15489334,
FT                                ECO:0000269|PubMed:17974005,
FT                                ECO:0000269|PubMed:19387438}.
FT                                /FTId=VAR_030493.
FT   VARIANT     734    734       G -> E (associated with SHEP10;
FT                                dbSNP:rs3829241).
FT                                {ECO:0000269|PubMed:15489334,
FT                                ECO:0000269|PubMed:17974005,
FT                                ECO:0000269|PubMed:18488028,
FT                                ECO:0000269|PubMed:19387438}.
FT                                /FTId=VAR_030494.
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
//
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