TPC1_RAT
ID TPC1_RAT Reviewed; 817 AA.
AC Q9WTN5; Q6P6R1;
DT 06-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2005, sequence version 2.
DT 03-AUG-2022, entry version 129.
DE RecName: Full=Two pore calcium channel protein 1;
DE AltName: Full=Voltage-dependent calcium channel protein TPC1;
GN Name=Tpcn1; Synonyms=Tpc1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], SUBUNIT, AND TISSUE SPECIFICITY.
RC TISSUE=Kidney;
RX PubMed=10753632; DOI=10.1006/bbrc.2000.2435;
RA Ishibashi K., Suzuki M., Imai M.;
RT "Molecular cloning of a novel form (two-repeat) protein related to voltage-
RT gated sodium and calcium channels.";
RL Biochem. Biophys. Res. Commun. 270:370-376(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
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).
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 voltage-gated highly-
CC selective Na(+) channel activated directly by PI(3,5)P2
CC (phosphatidylinositol 3,5-bisphosphate) that senses pH changes and
CC confers electrical excitability to organelles. Localizes to the early
CC and recycling endosomes membranes where it plays a role in the uptake
CC and processing of proteins and regulates organellar membrane
CC excitability, membrane trafficking and pH homeostasis. Ion selectivity
CC is 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 Required for mTOR-dependent nutrient sensing.
CC {ECO:0000250|UniProtKB:Q9ULQ1}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Na(+)(in) = Na(+)(out); Xref=Rhea:RHEA:34963,
CC ChEBI:CHEBI:29101; Evidence={ECO:0000250|UniProtKB:Q9ULQ1};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:34965;
CC Evidence={ECO:0000250|UniProtKB:Q9ULQ1};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Ca(2+)(in) = Ca(2+)(out); Xref=Rhea:RHEA:29671,
CC ChEBI:CHEBI:29108; Evidence={ECO:0000250|UniProtKB:Q9ULQ1};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:29673;
CC Evidence={ECO:0000250|UniProtKB:Q9ULQ1};
CC -!- ACTIVITY REGULATION: Na(+) current is inhibited by ATP in a MTORC-
CC dependent manner. ATP sensitivity is independent of PI(3,5)P2 (By
CC similarity). Probably regulated by Mg(2+) ions, cytosolic Mg(2+)
CC selectively inhibits outward current while lysosomal Mg(2+) modestly
CC inhibits both the outward and inward currents. In the absence of
CC Mg(2+), NAADP readily activates TPCN2, with properties similar to
CC PI(3,5)P2 (By similarity). Both current elicited by PI(3,5)P2 as well
CC as NAADP are inhibited by tetrandrine (By similarity).
CC {ECO:0000250|UniProtKB:Q8NHX9, ECO:0000250|UniProtKB:Q9ULQ1}.
CC -!- SUBUNIT: Dimer. Interacts with MTOR; the interaction is required for
CC TPCN1 ATP sensitivity (By similarity). Interacts with STX7, STX8 and
CC STX12 (By similarity). Interacts with JPT2 (By similarity). Found in a
CC complex with LSM12, TPCN1 and TPCN2 (By similarity).
CC {ECO:0000250|UniProtKB:Q9EQJ0, ECO:0000250|UniProtKB:Q9ULQ1}.
CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000250|UniProtKB:Q9ULQ1};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:Q9ULQ1}. Endosome
CC membrane {ECO:0000250|UniProtKB:Q9ULQ1}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9ULQ1}. Early endosome membrane
CC {ECO:0000250|UniProtKB:Q9EQJ0}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9EQJ0}. Recycling endosome membrane
CC {ECO:0000250|UniProtKB:Q9EQJ0}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9EQJ0}.
CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed at relatively high
CC level in kidney, liver and lung, and in the kidney it is expressed at
CC inner medullary collecting ducts. {ECO:0000269|PubMed:10753632}.
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 represent the voltage-sensor
CC and are characterized by a series of positively charged amino acids at
CC every third position. {ECO:0000250|UniProtKB:Q9ULQ1}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q9EQJ0}.
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; AB018253; BAA76556.2; -; mRNA.
DR EMBL; BC062072; AAH62072.1; -; mRNA.
DR PIR; JC7240; JC7240.
DR RefSeq; NP_647548.2; NM_139332.3.
DR AlphaFoldDB; Q9WTN5; -.
DR SMR; Q9WTN5; -.
DR STRING; 10116.ENSRNOP00000001866; -.
DR iPTMnet; Q9WTN5; -.
DR PhosphoSitePlus; Q9WTN5; -.
DR PRIDE; Q9WTN5; -.
DR GeneID; 246215; -.
DR KEGG; rno:246215; -.
DR UCSC; RGD:708494; rat.
DR CTD; 53373; -.
DR RGD; 708494; Tpcn1.
DR eggNOG; KOG2301; Eukaryota.
DR InParanoid; Q9WTN5; -.
DR OrthoDB; 761764at2759; -.
DR PhylomeDB; Q9WTN5; -.
DR Reactome; R-RNO-2672351; Stimuli-sensing channels.
DR PRO; PR:Q9WTN5; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0031901; C:early endosome membrane; ISS:UniProtKB.
DR GO; GO:0036019; C:endolysosome; ISS:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; ISO:RGD.
DR GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB.
DR GO; GO:0055038; C:recycling endosome membrane; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0097682; F:intracellular phosphatidylinositol-3,5-bisphosphate-sensitive cation channel activity; ISS:UniProtKB.
DR GO; GO:0015280; F:ligand-gated sodium channel activity; ISS:UniProtKB.
DR GO; GO:0072345; F:NAADP-sensitive calcium-release channel activity; ISS:UniProtKB.
DR GO; GO:0080025; F:phosphatidylinositol-3,5-bisphosphate binding; ISO:RGD.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0019905; F:syntaxin binding; ISO:RGD.
DR GO; GO:0005244; F:voltage-gated ion channel activity; IEA:UniProtKB-KW.
DR GO; GO:0005248; F:voltage-gated sodium channel activity; ISS:UniProtKB.
DR GO; GO:0075509; P:endocytosis involved in viral entry into host cell; ISO:RGD.
DR GO; GO:0010508; P:positive regulation of autophagy; ISO:RGD.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
DR GO; GO:0035725; P:sodium ion transmembrane transport; ISO:RGD.
DR Gene3D; 1.20.120.350; -; 1.
DR InterPro; IPR005821; Ion_trans_dom.
DR InterPro; IPR028801; TPC1_animal.
DR InterPro; IPR027359; Volt_channel_dom_sf.
DR PANTHER; PTHR46474; PTHR46474; 1.
DR Pfam; PF00520; Ion_trans; 2.
PE 1: Evidence at protein level;
KW Calcium; Calcium channel; Calcium transport; Coiled coil; Endosome;
KW Ion channel; Ion transport; Lysosome; Membrane; Reference proteome; Repeat;
KW Transmembrane; Transmembrane helix; Transport; Voltage-gated channel.
FT CHAIN 1..817
FT /note="Two pore calcium channel protein 1"
FT /id="PRO_0000276855"
FT TOPO_DOM 1..101
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 102..122
FT /note="Helical; Name=S1 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 123..137
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 138..158
FT /note="Helical; Name=S2 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 159..172
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 173..193
FT /note="Helical; Name=S3 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 194..202
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 203..221
FT /note="Helical; Name=S4 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 222..235
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 236..256
FT /note="Helical; Name=S5 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 257..263
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT INTRAMEM 264..287
FT /note="Helical; Pore-forming"
FT /evidence="ECO:0000255"
FT TOPO_DOM 288..298
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 299..319
FT /note="Helical; Name=S6 of repeat I"
FT /evidence="ECO:0000255"
FT TOPO_DOM 320..445
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 446..466
FT /note="Helical; Name=S1 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 467..480
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 481..501
FT /note="Helical; Name=S2 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 502..504
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 505..527
FT /note="Helical; Name=S3 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 528..535
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 536..550
FT /note="Helical; Name=S4 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 551..574
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 575..595
FT /note="Helical; Name=S5 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 596..630
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT INTRAMEM 631..654
FT /note="Helical; Pore-forming"
FT /evidence="ECO:0000255"
FT TOPO_DOM 655..671
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 672..692
FT /note="Helical; Name=S6 of repeat II"
FT /evidence="ECO:0000255"
FT TOPO_DOM 693..817
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 22..66
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 785..817
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 770..794
FT /evidence="ECO:0000255"
FT COMPBIAS 792..817
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ SEQUENCE 817 AA; 94405 MW; 0676FCF9D130DA46 CRC64;
MSVILDDDVL LILTLDEELS APLTPSNGLG QEDLPSKNGG GQSGPNSQVP SLVSGADSPP
SSPPGHNWEM NYQEAAIYLQ EGQNNDKFFT HPKDARALAA YLFVHNHFFY MMELLTALLL
LLLSLCESPA VPALKLRTYV HATLELFALM VVVFELCMKL RWLGFHTFVR HKRTMVKTSV
LVVQFIEAIV VLVRQTSHVR VTRALRCIFL VDCRYCGGVR RNLRQIFQSL PPFMDILLLL
LFFMIIFAIL GFYLFSTNPS DPYFNTLENS IVNLFVLLTT ANFPDVMMPS YSRNPWSCVF
FIVYLSIELY FIMNLLLAVV FDTFNDIEKH KFKSLLLHKR TAIQHAYHLL VSQRRPAGIS
YRQFEGLMRF YKPRMSARER FLTFKALNQS NTPLLSLKDF YDIYEVAALQ WKAKKNRQHW
FDELPRTAFL IFKGINILVN SKAFQYFMYL VVAVNGVWIL VETFMLKGGN FISKHVPWSY
LVFLTIYGVE LFMKVAGLGP VEYLSSGWNL FDFSVTAFAF LGLLALTLNM EPFYFIVVLR
PLQLLRLFKL KKRYRNVLDT MFELLPRMAS LGLTLLTFYY SFAIVGMEFF SGRLSPNCCN
SSTVADAYRF INHTVGNKTK VEEGYYYLNN FDNILNSFVT LFELTVVNNW YIIMEGVTSQ
TSHWSRLYFM TFYIVTMVVM TIIVAFILEA FVFRMNYSRK SQESEVDSGI VIEKEMSKEE
LLAILELHRE ARGTSSDVTR LLDTLSQMEK YQQNSMVFLG RRSRTKSDLS LKMYQEEIQE
WYEEHAREQE QQQLRGSAPS PAAQQTPGSR QRSQTVT
