TM175_MOUSE
ID TM175_MOUSE Reviewed; 499 AA.
AC Q9CXY1; Q3TDC4; Q99K00;
DT 03-APR-2007, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2007, sequence version 2.
DT 03-AUG-2022, entry version 118.
DE RecName: Full=Endosomal/lysosomal potassium channel TMEM175 {ECO:0000305};
DE AltName: Full=Transmembrane protein 175 {ECO:0000303|PubMed:26317472};
DE Short=mTMEM175 {ECO:0000303|PubMed:26317472};
GN Name=Tmem175 {ECO:0000303|PubMed:26317472, ECO:0000312|MGI:MGI:1919642};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Dendritic cell, and Head;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Czech II; TISSUE=Mammary tumor;
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 [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
RN [4]
RP FUNCTION.
RX PubMed=26317472; DOI=10.1016/j.cell.2015.08.002;
RA Cang C., Aranda K., Seo Y.J., Gasnier B., Ren D.;
RT "TMEM175 is an organelle K(+) channel regulating lysosomal function.";
RL Cell 162:1101-1112(2015).
RN [5]
RP FUNCTION, ACTIVITY REGULATION, IDENTIFICATION IN THE LYSOK(GF) COMPLEX,
RP DISRUPTION PHENOTYPE, AND MUTAGENESIS OF GLN-62 AND ILE-390.
RX PubMed=33505021; DOI=10.1038/s41586-021-03185-z;
RA Wie J., Liu Z., Song H., Tropea T.F., Yang L., Wang H., Liang Y., Cang C.,
RA Aranda K., Lohmann J., Yang J., Lu B., Chen-Plotkin A.S., Luk K.C., Ren D.;
RT "A growth-factor-activated lysosomal K+ channel regulates Parkinson's
RT pathology.";
RL Nature 591:431-437(2021).
CC -!- FUNCTION: Organelle-specific potassium channel specifically responsible
CC for potassium conductance in endosomes and lysosomes (PubMed:26317472,
CC PubMed:33505021). Forms a potassium-permeable leak-like channel, which
CC regulates lumenal pH stability and is required for autophagosome-
CC lysosome fusion (PubMed:26317472). Constitutes the major lysosomal
CC potassium channel (By similarity). Constitutes the pore-forming subunit
CC of the lysoK(GF) complex, a complex activated by extracellular growth
CC factors (PubMed:33505021). The lysoK(GF) complex is composed of TMEM175
CC and AKT (AKT1, AKT2 or AKT3), a major target of growth factor
CC receptors: in the complex, TMEM175 channel is opened by conformational
CC changes by AKT, leading to its activation (PubMed:33505021). The
CC lysoK(GF) complex is required to protect neurons against stress-induced
CC damage (PubMed:33505021). {ECO:0000250|UniProtKB:Q9BSA9,
CC ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:33505021}.
CC -!- ACTIVITY REGULATION: Channel activity is activated following
CC interaction with AKT (AKT1, AKT2 or AKT3): interaction promotes
CC activation from closed to an open state. Activation by AKT is
CC independent of AKT serine/threonine-protein kinase activity.
CC {ECO:0000269|PubMed:33505021}.
CC -!- SUBUNIT: Homodimer (By similarity). Interacts with AKT (AKT1, AKT2 or
CC AKT3); leading to formation of the lysoK(GF) complex, which activates
CC the channel (PubMed:33505021). {ECO:0000250|UniProtKB:Q9BSA9,
CC ECO:0000269|PubMed:33505021}.
CC -!- SUBCELLULAR LOCATION: Endosome membrane {ECO:0000250|UniProtKB:Q9BSA9};
CC Multi-pass membrane protein {ECO:0000255}. Lysosome membrane
CC {ECO:0000250|UniProtKB:Q9BSA9}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- DOMAIN: Composed of two modules of six transmembranes, forming a
CC homodimer with a tetrameric architecture. The six transmembrane regions
CC of each module are tightly packed within each subunit without
CC undergoing domain swapping. Forms a central ion-conduction pore lined
CC by the side chains of the pore-lining helices. Conserved isoleucine
CC residues (Ile-43 in the first module and Ile-268 in the second module)
CC in the center of the pore serve as the gate in the closed conformation.
CC In the widened channel in the open conformation, the same residues
CC establish a constriction essential for potassium selectivity.
CC {ECO:0000250|UniProtKB:Q9BSA9}.
CC -!- DISRUPTION PHENOTYPE: Mice display accelerated loss of dopaminergic
CC neurons and impaired motor skills (PubMed:33505021). Knockout neurons
CC show increased damage in response to insults and an accumulation of
CC alpha-synuclein (PubMed:33505021). The accumulation of alpha-synuclein
CC leads to increased damage to the integrity of lysosomal membranes
CC (PubMed:33505021). {ECO:0000269|PubMed:33505021}.
CC -!- SIMILARITY: Belongs to the TMEM175 family. {ECO:0000305}.
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DR EMBL; AK013879; BAB29031.1; -; mRNA.
DR EMBL; AK170273; BAE41678.1; -; mRNA.
DR EMBL; BC005542; AAH05542.1; -; mRNA.
DR CCDS; CCDS19514.1; -.
DR RefSeq; NP_001157004.1; NM_001163532.1.
DR RefSeq; NP_082499.3; NM_028223.3.
DR RefSeq; XP_006535292.1; XM_006535229.2.
DR RefSeq; XP_006535293.1; XM_006535230.3.
DR AlphaFoldDB; Q9CXY1; -.
DR SMR; Q9CXY1; -.
DR STRING; 10090.ENSMUSP00000068607; -.
DR iPTMnet; Q9CXY1; -.
DR PhosphoSitePlus; Q9CXY1; -.
DR EPD; Q9CXY1; -.
DR MaxQB; Q9CXY1; -.
DR PaxDb; Q9CXY1; -.
DR PRIDE; Q9CXY1; -.
DR ProteomicsDB; 259540; -.
DR Antibodypedia; 8167; 63 antibodies from 21 providers.
DR DNASU; 72392; -.
DR Ensembl; ENSMUST00000063272; ENSMUSP00000068607; ENSMUSG00000013495.
DR Ensembl; ENSMUST00000078323; ENSMUSP00000077437; ENSMUSG00000013495.
DR Ensembl; ENSMUST00000120327; ENSMUSP00000112780; ENSMUSG00000013495.
DR GeneID; 72392; -.
DR KEGG; mmu:72392; -.
DR UCSC; uc008yoq.2; mouse.
DR CTD; 84286; -.
DR MGI; MGI:1919642; Tmem175.
DR VEuPathDB; HostDB:ENSMUSG00000013495; -.
DR eggNOG; ENOG502QR5C; Eukaryota.
DR GeneTree; ENSGT00390000015667; -.
DR HOGENOM; CLU_052593_0_0_1; -.
DR InParanoid; Q9CXY1; -.
DR OMA; FFFPVSY; -.
DR OrthoDB; 894975at2759; -.
DR PhylomeDB; Q9CXY1; -.
DR TreeFam; TF328838; -.
DR BioGRID-ORCS; 72392; 4 hits in 73 CRISPR screens.
DR PRO; PR:Q9CXY1; -.
DR Proteomes; UP000000589; Chromosome 5.
DR RNAct; Q9CXY1; protein.
DR Bgee; ENSMUSG00000013495; Expressed in spermatocyte and 205 other tissues.
DR ExpressionAtlas; Q9CXY1; baseline and differential.
DR Genevisible; Q9CXY1; MM.
DR GO; GO:0005768; C:endosome; ISS:UniProtKB.
DR GO; GO:0031303; C:integral component of endosome membrane; ISS:UniProtKB.
DR GO; GO:1905103; C:integral component of lysosomal membrane; ISS:UniProtKB.
DR GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR GO; GO:0005267; F:potassium channel activity; ISS:UniProtKB.
DR GO; GO:0022841; F:potassium ion leak channel activity; IMP:UniProtKB.
DR GO; GO:0070050; P:neuron cellular homeostasis; IMP:UniProtKB.
DR GO; GO:0090385; P:phagosome-lysosome fusion; IMP:UniProtKB.
DR GO; GO:0071805; P:potassium ion transmembrane transport; IMP:UniProtKB.
DR GO; GO:0035751; P:regulation of lysosomal lumen pH; IMP:UniProtKB.
DR InterPro; IPR010617; TMEM175.
DR Pfam; PF06736; TMEM175; 2.
PE 1: Evidence at protein level;
KW Endosome; Ion channel; Ion transport; Lysosome; Membrane; Phosphoprotein;
KW Potassium; Potassium channel; Potassium transport; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..499
FT /note="Endosomal/lysosomal potassium channel TMEM175"
FT /id="PRO_0000282589"
FT TOPO_DOM 1..30
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 31..53
FT /note="Helical; Name=TM1-1"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TOPO_DOM 54..74
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 75..97
FT /note="Helical; Name=TM2-1"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TOPO_DOM 98..103
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 104..125
FT /note="Helical; Name=TM3-1"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TOPO_DOM 126..135
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 136..157
FT /note="Helical; Name=TM4-1"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TOPO_DOM 158..181
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 182..202
FT /note="Helical; Name=TM5-1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 203..207
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 208..227
FT /note="Helical; Name=TM6-1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 228..254
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 255..279
FT /note="Helical; Name=TM1-2"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TOPO_DOM 280..306
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 307..329
FT /note="Helical; Name=TM2-2"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TOPO_DOM 330..335
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 336..357
FT /note="Helical; Name=TM3-2"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TOPO_DOM 358..372
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 373..393
FT /note="Helical; Name=TM4-2"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TOPO_DOM 394..413
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 414..437
FT /note="Helical; Name=TM5-2"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TOPO_DOM 438..439
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TRANSMEM 440..466
FT /note="Helical; Name=TM6-2"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT TOPO_DOM 467..499
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT REGION 1..30
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 55..60
FT /note="Short helix H1-1"
FT /evidence="ECO:0000250|UniProtKB:K9UJK2"
FT REGION 62..68
FT /note="Short helix H2-1"
FT /evidence="ECO:0000250|UniProtKB:K9UJK2"
FT REGION 285..293
FT /note="Short helix H1-2"
FT /evidence="ECO:0000250|UniProtKB:K9UJK2"
FT REGION 295..301
FT /note="Short helix H2-2"
FT /evidence="ECO:0000250|UniProtKB:K9UJK2"
FT MOTIF 32..38
FT /note="RxxxFSD motif 1"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT MOTIF 257..263
FT /note="RxxxFSD motif 2"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT COMPBIAS 9..28
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 43
FT /note="Hydrophobic filter residue 1-1"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT SITE 47
FT /note="Hydrophobic filter residue 2-1"
FT /evidence="ECO:0000250|UniProtKB:K9UJK2"
FT SITE 50
FT /note="Hydrophobic filter residue 3-1"
FT /evidence="ECO:0000250|UniProtKB:K9UJK2"
FT SITE 268
FT /note="Hydrophobic filter residue 1-2"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT SITE 272
FT /note="Hydrophobic filter residue 2-2"
FT /evidence="ECO:0000250|UniProtKB:K9UJK2"
FT SITE 275
FT /note="Hydrophobic filter residue 3-2"
FT /evidence="ECO:0000250|UniProtKB:K9UJK2"
FT MOD_RES 6
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9BSA9"
FT MUTAGEN 62
FT /note="Q->P: Gain-of-function mutant; increased potassium
FT channel activity in knockin mice."
FT /evidence="ECO:0000269|PubMed:33505021"
FT MUTAGEN 390
FT /note="I->T: Reduced potassium channel activity in knockin
FT mice."
FT /evidence="ECO:0000269|PubMed:33505021"
FT CONFLICT 174
FT /note="H -> R (in Ref. 2; AAH05542)"
FT /evidence="ECO:0000305"
FT CONFLICT 197
FT /note="A -> S (in Ref. 1; BAE41678)"
FT /evidence="ECO:0000305"
FT CONFLICT 324
FT /note="H -> R (in Ref. 1; BAE41678)"
FT /evidence="ECO:0000305"
FT CONFLICT 475
FT /note="G -> R (in Ref. 1; BAB29031)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 499 AA; 55578 MW; BDED3561EF10EB92 CRC64;
MSRLQTEEQA VDSEGDSSLH RRNEEGTQSS HRMLGFSDAL LSIIATVMIL PVTHTEISPE
QQFDKSIQKL LATRIAVYLM TFLIVTVAWT AHTRLFQVVG KIDDTLALLN LACMMTITLL
PYTFSLMVTF PDVPLGIFLF CVCVIAIGSV QAMIVGYAFH FPHLLNPQIQ CSTHRDLSRR
HILHLVLRGP ALCFVAAVFS LFFFPLSYLL MVTVIFLPHI SKATTWCKDK LMGQRESPAH
DMEPFSIDLH APLSKERVEA FSDGVYAIVA TLLILDICED NVPDPKDVQE KFSGSLVAAL
GAYGPQFLAY FGSFATVGLL WFAHHSLFLH VRKATQTMGL LNILSLAFVG GLPLAYQQTS
AFARQPHDEL ERVRVSCAII FFASIFQFAI WTTALLHQTE TLQPAVQFGG QEHAFMFAKL
ALYPCASLLA FAATCLLSRF STAIFHLMQI SVPFAFLLLR LLVRLALAGL QVLRGLWPHH
PQQDQSEPEA QSQLLPDPC
