ID TM175_HUMAN Reviewed; 504 AA. AC Q9BSA9; D3DVN4; Q8ND13; DT 03-APR-2007, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 27-MAR-2024, entry version 140. DE RecName: Full=Endosomal/lysosomal proton channel TMEM175 {ECO:0000305}; DE AltName: Full=Potassium channel TMEM175 {ECO:0000305}; DE AltName: Full=Transmembrane protein 175 {ECO:0000303|PubMed:26317472}; DE Short=hTMEM175 {ECO:0000303|PubMed:26317472, ECO:0000303|PubMed:28723891, ECO:0000303|PubMed:32228865}; GN Name=TMEM175 {ECO:0000303|PubMed:26317472, GN ECO:0000312|HGNC:HGNC:28709}; 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 [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; 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 [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Kidney; 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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-6, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [5] RP FUNCTION, TRANSPORTER ACTIVITY, DOMAIN, SUBCELLULAR LOCATION, TOPOLOGY, RP TISSUE SPECIFICITY, AND MUTAGENESIS OF ARG-35; PHE-39; SER-40 AND ASP-41. 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 [6] RP FUNCTION, TRANSPORTER ACTIVITY, SUBUNIT, DOMAIN, AND MUTAGENESIS OF ILE-46; RP VAL-50; LEU-53; ILE-271; LEU-275 AND LEU-278. RX PubMed=28723891; DOI=10.1038/nature23269; RA Lee C., Guo J., Zeng W., Kim S., She J., Cang C., Ren D., Jiang Y.; RT "The lysosomal potassium channel TMEM175 adopts a novel tetrameric RT architecture."; RL Nature 547:472-475(2017). RN [7] RP POSSIBLE INVOLVEMENT IN PARK. RX PubMed=28193887; DOI=10.1073/pnas.1616332114; RA Jinn S., Drolet R.E., Cramer P.E., Wong A.H., Toolan D.M., Gretzula C.A., RA Voleti B., Vassileva G., Disa J., Tadin-Strapps M., Stone D.J.; RT "TMEM175 deficiency impairs lysosomal and mitochondrial function and RT increases alpha-synuclein aggregation."; RL Proc. Natl. Acad. Sci. U.S.A. 114:2389-2394(2017). RN [8] RP SUBCELLULAR LOCATION, INVOLVEMENT IN PARK, VARIANTS PRO-65 AND THR-393, AND RP CHARACTERIZATION OF VARIANTS PRO-65 AND THR-393. RX PubMed=31658403; DOI=10.1002/ana.25629; RA Krohn L., Oeztuerk T.N., Vanderperre B., Ouled Amar Bencheikh B., RA Ruskey J.A., Laurent S.B., Spiegelman D., Postuma R.B., Arnulf I., RA Hu M.T.M., Dauvilliers Y., Hoegl B., Stefani A., Monaca C.C., Plazzi G., RA Antelmi E., Ferini-Strambi L., Heidbreder A., Rudakou U., RA Cochen De Cock V., Young P., Wolf P., Oliva P., Zhang X.K., Greenbaum L., RA Liong C., Gagnon J.F., Desautels A., Hassin-Baer S., Montplaisir J.Y., RA Dupre N., Rouleau G.A., Fon E.A., Trempe J.F., Lamoureux G., Alcalay R.N., RA Gan-Or Z.; RT "Genetic, structural, and functional evidence link TMEM175 to RT synucleinopathies."; RL Ann. Neurol. 87:139-153(2020). RN [9] RP SUBCELLULAR LOCATION, INVOLVEMENT IN PARK, VARIANT THR-393, AND RP CHARACTERIZATION OF VARIANT THR-393. RX PubMed=31261387; DOI=10.1093/hmg/ddz136; RA Jinn S., Blauwendraat C., Toolan D., Gretzula C.A., Drolet R.E., Smith S., RA Nalls M.A., Marcus J., Singleton A.B., Stone D.J.; RT "Functionalization of the TMEM175 p.M393T variant as a risk factor for RT Parkinson disease."; RL Hum. Mol. Genet. 28:3244-3254(2019). RN [10] RP FUNCTION, TRANSPORTER ACTIVITY, AND MUTAGENESIS OF 45-SER--THR-49; THR-49 RP AND THR-274. RX PubMed=32267231; DOI=10.7554/elife.53683; RA Brunner J.D., Jakob R.P., Schulze T., Neldner Y., Moroni A., Thiel G., RA Maier T., Schenck S.; RT "Structural basis for ion selectivity in TMEM175 K+ channels."; RL Elife 9:0-0(2020). RN [11] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH AKT1, RP IDENTIFICATION IN THE LYSOK(GF) COMPLEX, INVOLVEMENT IN PARK, RP CHARACTERIZATION OF VARIANTS PRO-65 AND THR-393, AND MUTAGENESIS OF RP SER-241; THR-338 AND MET-393. 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). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF RP ASP-41 AND SER-45. RX PubMed=35750034; DOI=10.1016/j.cell.2022.05.021; RA Hu M., Li P., Wang C., Feng X., Geng Q., Chen W., Marthi M., Zhang W., RA Gao C., Reid W., Swanson J., Du W., Hume R.I., Xu H.; RT "Parkinson's disease-risk protein TMEM175 is a proton-activated proton RT channel in lysosomes."; RL Cell 185:2292-2308(2022). RN [13] RP FUNCTION, TRANSPORTER ACTIVITY, AND MUTAGENESIS OF SER-38; SER-45; ILE-46; RP THR-49; ILE-271; THR-274; ASP-279; ASP-283; ARG-309; HIS-327; HIS-328; RP ASN-345; GLN-360 AND HIS-449. RX PubMed=35333573; DOI=10.1126/sciadv.abm1568; RA Zheng W., Shen C., Wang L., Rawson S., Xie W.J., Nist-Lund C., Wu J., RA Shen Z., Xia S., Holt J.R., Wu H., Fu T.M.; RT "pH regulates potassium conductance and drives a constitutive proton RT current in human TMEM175."; RL Sci. Adv. 8:eabm1568-eabm1568(2022). RN [14] {ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC} RP STRUCTURE BY ELECTRON MICROSCOPY (2.64 ANGSTROMS), FUNCTION, TRANSPORTER RP ACTIVITY, SUBCELLULAR LOCATION, SUBUNIT, DOMAIN, AND MUTAGENESIS OF SER-45 RP AND THR-274. RX PubMed=32228865; DOI=10.7554/elife.53430; RA Oh S., Paknejad N., Hite R.K.; RT "Gating and selectivity mechanisms for the lysosomal K+ channel TMEM175."; RL Elife 9:0-0(2020). RN [15] RP STRUCTURE BY ELECTRON MICROSCOPY (2.45 ANGSTROMS), FUNCTION, SUBUNIT, AND RP MUTAGENESIS OF ILE-46 AND ILE-271. RX PubMed=35608336; DOI=10.7554/elife.75122; RA Oh S., Marinelli F., Zhou W., Lee J., Choi H.J., Kim M., RA Faraldo-Gomez J.D., Hite R.K.; RT "Differential ion dehydration energetics explains selectivity in the non- RT canonical lysosomal K+ channel TMEM175."; RL Elife 11:0-0(2022). RN [16] {ECO:0007744|PDB:8FY5} RP STRUCTURE BY ELECTRON MICROSCOPY (3.4 ANGSTROMS) IN COMPLEX WITH LAMP1, RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH LAMP1 RP AND LAMP2, AND MUTAGENESIS OF THR-395. RX PubMed=37390818; DOI=10.1016/j.molcel.2023.06.004; RA Zhang J., Zeng W., Han Y., Lee W.R., Liou J., Jiang Y.; RT "Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the RT TMEM175 channel."; RL Mol. Cell 83:2524-2539(2023). CC -!- FUNCTION: Proton-activated proton channel that catalyzes proton efflux CC from endosomes and lysosomes to maintain a steady-state pH CC (PubMed:35750034, PubMed:35333573, PubMed:37390818). Activated at low CC pH (under pH 4.6) by luminal side protons: selectively mediates CC lysosomal proton release from lysosomes, eliciting a proton leak that CC balances V-ATPase activity to maintain pH homeostasis CC (PubMed:35750034). Regulation of lumenal pH stability is required for CC autophagosome-lysosome fusion (PubMed:26317472, PubMed:32267231). Also CC acts as a potassium channel at higher pH, regulating potassium CC conductance in endosomes and lysosomes (PubMed:26317472, CC PubMed:28723891, PubMed:32228865, PubMed:32267231, PubMed:33505021). CC Constitutes the pore-forming subunit of the lysoK(GF) complex, a CC complex activated by extracellular growth factors (PubMed:33505021). CC The lysoK(GF) complex is composed of TMEM175 and AKT (AKT1, AKT2 or CC AKT3), a major target of growth factor receptors: in the complex, CC TMEM175 channel is opened by conformational changes by AKT, leading to CC its activation (PubMed:33505021). The lysoK(GF) complex is required to CC protect neurons against stress-induced damage (PubMed:33505021). CC {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:28723891, CC ECO:0000269|PubMed:32228865, ECO:0000269|PubMed:32267231, CC ECO:0000269|PubMed:33505021, ECO:0000269|PubMed:35333573, CC ECO:0000269|PubMed:35750034, ECO:0000269|PubMed:37390818}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+)(in) = H(+)(out); Xref=Rhea:RHEA:34979, ChEBI:CHEBI:15378; CC Evidence={ECO:0000269|PubMed:35750034, ECO:0000269|PubMed:37390818}; CC -!- CATALYTIC ACTIVITY: CC Reaction=K(+)(in) = K(+)(out); Xref=Rhea:RHEA:29463, ChEBI:CHEBI:29103; CC Evidence={ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:28723891, CC ECO:0000269|PubMed:32228865, ECO:0000269|PubMed:32267231, CC ECO:0000269|PubMed:33505021}; CC -!- ACTIVITY REGULATION: Active at low pH (under pH 4.6): proton channel CC activity is activated by luminal side protons (PubMed:35750034). CC Polyunsaturated fatty acids, such as arachidonic acid, also activate CC the channel activity (PubMed:35750034). Proton channel activity is CC directly inhibited by LAMP1 or LAMP2, facilitating lysosomal CC acidification (PubMed:37390818). Channel activity is activated CC following interaction with AKT (AKT1, AKT2 or AKT3): interaction CC promotes activation from closed to an open state (PubMed:33505021). CC Activation by AKT is independent of AKT serine/threonine-protein kinase CC activity (PubMed:33505021). {ECO:0000269|PubMed:33505021, CC ECO:0000269|PubMed:35750034, ECO:0000269|PubMed:37390818}. CC -!- SUBUNIT: Homodimer (PubMed:28723891, PubMed:32228865, PubMed:35608336). CC Interacts with AKT (AKT1, AKT2 or AKT3); leading to formation of the CC lysoK(GF) complex, which activates the channel (PubMed:33505021). CC Interacts with LAMP1; inhibiting the proton channel activity of TMEM175 CC (PubMed:37390818). Interacts with LAMP2; inhibiting the proton channel CC activity of TMEM175 (PubMed:37390818). {ECO:0000269|PubMed:32228865, CC ECO:0000269|PubMed:33505021, ECO:0000269|PubMed:35608336, CC ECO:0000269|PubMed:37390818, ECO:0000305|PubMed:28723891}. CC -!- SUBCELLULAR LOCATION: Endosome membrane {ECO:0000269|PubMed:26317472, CC ECO:0000269|PubMed:32228865}; Multi-pass membrane protein CC {ECO:0000269|PubMed:32228865}. Lysosome membrane CC {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:31261387, CC ECO:0000269|PubMed:31658403, ECO:0000269|PubMed:32228865}; Multi-pass CC membrane protein {ECO:0000269|PubMed:32228865}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9BSA9-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9BSA9-2; Sequence=VSP_024213; CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:26317472}. CC -!- DOMAIN: Composed of two modules of six transmembranes, forming a CC homodimer with a tetrameric architecture (PubMed:28723891, CC PubMed:32228865). The six transmembrane regions of each module are CC tightly packed within each subunit without undergoing domain swapping CC (PubMed:32228865). Forms a central ion-conduction pore lined by the CC side chains of the pore-lining helices (PubMed:32228865). Conserved CC isoleucine residues (Ile-46 in the first module and Ile-271 in the CC second module) in the center of the pore serve as the gate in the CC closed conformation (PubMed:32228865). In the widened channel in the CC open conformation, Ser-45 and Ile-46 in the first module (and Thr-274 CC and Ile-271 in the second module), establish a constriction essential CC for potassium selectivity (PubMed:32228865). CC {ECO:0000269|PubMed:28723891, ECO:0000269|PubMed:32228865}. CC -!- DISEASE: Parkinson disease (PARK) [MIM:168600]: A complex CC neurodegenerative disorder characterized by bradykinesia, resting CC tremor, muscular rigidity and postural instability. Additional features CC are characteristic postural abnormalities, dysautonomia, dystonic CC cramps, and dementia. The pathology of Parkinson disease involves the CC loss of dopaminergic neurons in the substantia nigra and the presence CC of Lewy bodies (intraneuronal accumulations of aggregated proteins), in CC surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, although CC early-onset cases (before 50 years) are known. The majority of the CC cases are sporadic suggesting a multifactorial etiology based on CC environmental and genetic factors. However, some patients present with CC a positive family history for the disease. Familial forms of the CC disease usually begin at earlier ages and are associated with atypical CC clinical features. {ECO:0000269|PubMed:28193887, CC ECO:0000269|PubMed:31261387, ECO:0000269|PubMed:31658403, CC ECO:0000269|PubMed:33505021}. Note=Disease susceptibility may be CC associated with variants affecting the gene represented in this entry. CC TMEM175 defects result in unstable lysosomal pH, leading to decreased CC lysosomal catalytic activity, decreased glucocerebrosidase activity, CC impaired autophagosome clearance by the lysosome and decreased CC mitochondrial respiration (PubMed:28193887). CC {ECO:0000269|PubMed:28193887}. CC -!- SIMILARITY: Belongs to the TMEM175 family. {ECO:0000305}. CC -!- CAUTION: A publication claims that potassium transport was initially CC measured with a luminal side pH above 7.0, which is non-physiological CC for lysosomal channels (PubMed:35750034). This statement is however CC incorrect as potassium transport was tested at lumenal pH of 5.5, which CC is considered physiological (PubMed:26317472). CC {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:35750034}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AL834199; CAD38888.1; -; mRNA. DR EMBL; CH471131; EAW82633.1; -; Genomic_DNA. DR EMBL; CH471131; EAW82638.1; -; Genomic_DNA. DR EMBL; BC005158; AAH05158.1; -; mRNA. DR CCDS; CCDS3341.1; -. [Q9BSA9-1] DR CCDS; CCDS75088.1; -. [Q9BSA9-2] DR RefSeq; NP_001284355.1; NM_001297426.1. [Q9BSA9-2] DR RefSeq; NP_001284356.1; NM_001297427.1. [Q9BSA9-2] DR RefSeq; NP_001284357.1; NM_001297428.1. [Q9BSA9-2] DR RefSeq; NP_115702.1; NM_032326.3. [Q9BSA9-1] DR RefSeq; XP_005272361.1; XM_005272304.1. DR RefSeq; XP_016864190.1; XM_017008701.1. [Q9BSA9-1] DR RefSeq; XP_016864194.1; XM_017008705.1. DR PDB; 6W8N; EM; 3.20 A; A/B=1-504. DR PDB; 6W8O; EM; 3.40 A; A/B=1-504. DR PDB; 6W8P; EM; 3.60 A; A/B=1-504. DR PDB; 6WC9; EM; 2.64 A; A/B=1-504. DR PDB; 6WCA; EM; 3.03 A; A/B=1-504. DR PDB; 6WCB; EM; 3.17 A; A/B=1-504. DR PDB; 6WCC; EM; 3.24 A; A/B=1-504. DR PDB; 7LF6; EM; 3.50 A; A/B=1-504. DR PDB; 7UNL; EM; 2.45 A; A/B=1-504. DR PDB; 7UNM; EM; 2.61 A; A/B=1-504. DR PDB; 8DHM; EM; 2.73 A; A/B=1-504. DR PDB; 8FY5; EM; 3.40 A; A/B=1-504. DR PDB; 8FYF; EM; 3.40 A; A/B=1-504. DR PDBsum; 6W8N; -. DR PDBsum; 6W8O; -. DR PDBsum; 6W8P; -. DR PDBsum; 6WC9; -. DR PDBsum; 6WCA; -. DR PDBsum; 6WCB; -. DR PDBsum; 6WCC; -. DR PDBsum; 7LF6; -. DR PDBsum; 7UNL; -. DR PDBsum; 7UNM; -. DR PDBsum; 8DHM; -. DR PDBsum; 8FY5; -. DR PDBsum; 8FYF; -. DR AlphaFoldDB; Q9BSA9; -. DR EMDB; EMD-21575; -. DR EMDB; EMD-21576; -. DR EMDB; EMD-21577; -. DR EMDB; EMD-21603; -. DR EMDB; EMD-21604; -. DR EMDB; EMD-21605; -. DR EMDB; EMD-21606; -. DR EMDB; EMD-23300; -. DR EMDB; EMD-26626; -. DR EMDB; EMD-26627; -. DR EMDB; EMD-27436; -. DR EMDB; EMD-29553; -. DR EMDB; EMD-29572; -. DR SMR; Q9BSA9; -. DR BioGRID; 124013; 8. DR IntAct; Q9BSA9; 5. DR MINT; Q9BSA9; -. DR STRING; 9606.ENSP00000264771; -. DR TCDB; 1.A.78.1.1; the k+-selective channel in endosomes and lysosomes (kel) family. DR iPTMnet; Q9BSA9; -. DR PhosphoSitePlus; Q9BSA9; -. DR SwissPalm; Q9BSA9; -. DR BioMuta; TMEM175; -. DR DMDM; 74732981; -. DR EPD; Q9BSA9; -. DR jPOST; Q9BSA9; -. DR MassIVE; Q9BSA9; -. DR MaxQB; Q9BSA9; -. DR PaxDb; 9606-ENSP00000264771; -. DR PeptideAtlas; Q9BSA9; -. DR ProteomicsDB; 78871; -. [Q9BSA9-1] DR ProteomicsDB; 78872; -. [Q9BSA9-2] DR Antibodypedia; 8167; 84 antibodies from 21 providers. DR DNASU; 84286; -. DR Ensembl; ENST00000264771.9; ENSP00000264771.4; ENSG00000127419.17. [Q9BSA9-1] DR Ensembl; ENST00000515740.5; ENSP00000427039.1; ENSG00000127419.17. [Q9BSA9-2] DR Ensembl; ENST00000622959.3; ENSP00000485461.1; ENSG00000127419.17. [Q9BSA9-2] DR GeneID; 84286; -. DR KEGG; hsa:84286; -. DR MANE-Select; ENST00000264771.9; ENSP00000264771.4; NM_032326.4; NP_115702.1. DR UCSC; uc003gbq.4; human. [Q9BSA9-1] DR AGR; HGNC:28709; -. DR CTD; 84286; -. DR DisGeNET; 84286; -. DR GeneCards; TMEM175; -. DR HGNC; HGNC:28709; TMEM175. DR HPA; ENSG00000127419; Low tissue specificity. DR MIM; 168600; phenotype. DR MIM; 616660; gene. DR neXtProt; NX_Q9BSA9; -. DR OpenTargets; ENSG00000127419; -. DR PharmGKB; PA162405946; -. DR VEuPathDB; HostDB:ENSG00000127419; -. DR eggNOG; ENOG502QR5C; Eukaryota. DR GeneTree; ENSGT00390000015667; -. DR InParanoid; Q9BSA9; -. DR OMA; FFFPVSY; -. DR OrthoDB; 5353701at2759; -. DR PhylomeDB; Q9BSA9; -. DR TreeFam; TF328838; -. DR PathwayCommons; Q9BSA9; -. DR SignaLink; Q9BSA9; -. DR BioGRID-ORCS; 84286; 16 hits in 1152 CRISPR screens. DR ChiTaRS; TMEM175; human. DR GenomeRNAi; 84286; -. DR Pharos; Q9BSA9; Tbio. DR PRO; PR:Q9BSA9; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q9BSA9; Protein. DR Bgee; ENSG00000127419; Expressed in right hemisphere of cerebellum and 157 other cell types or tissues. DR ExpressionAtlas; Q9BSA9; baseline and differential. DR GO; GO:0005768; C:endosome; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:UniProtKB. DR GO; GO:0050544; F:arachidonic acid binding; IDA:UniProtKB. DR GO; GO:0005267; F:potassium channel activity; IDA:UniProtKB. DR GO; GO:0022841; F:potassium ion leak channel activity; IDA:UniProtKB. DR GO; GO:0015252; F:proton channel activity; IDA:UniProtKB. DR GO; GO:0035752; P:lysosomal lumen pH elevation; IDA:UniProtKB. DR GO; GO:0070050; P:neuron cellular homeostasis; ISS:UniProtKB. DR GO; GO:0090385; P:phagosome-lysosome fusion; IEA:Ensembl. DR GO; GO:0071805; P:potassium ion transmembrane transport; IDA:UniProtKB. DR GO; GO:1902600; P:proton transmembrane transport; IDA:UniProtKB. DR GO; GO:0035751; P:regulation of lysosomal lumen pH; IDA:UniProt. DR InterPro; IPR010617; TMEM175-like. DR PANTHER; PTHR31462; ENDOSOMAL/LYSOSOMAL POTASSIUM CHANNEL TMEM175; 1. DR PANTHER; PTHR31462:SF5; ENDOSOMAL_LYSOSOMAL POTASSIUM CHANNEL TMEM175; 1. DR Pfam; PF06736; TMEM175; 2. DR Genevisible; Q9BSA9; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Endosome; Hydrogen ion transport; KW Ion channel; Ion transport; Lysosome; Membrane; Neurodegeneration; KW Parkinson disease; Parkinsonism; Phosphoprotein; Potassium; KW Potassium channel; Potassium transport; Reference proteome; Transmembrane; KW Transmembrane helix; Transport. FT CHAIN 1..504 FT /note="Endosomal/lysosomal proton channel TMEM175" FT /id="PRO_0000282588" FT TOPO_DOM 1..33 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26317472" FT TRANSMEM 34..56 FT /note="Helical; Name=TM1-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 57..77 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 78..100 FT /note="Helical; Name=TM2-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 101..106 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 107..128 FT /note="Helical; Name=TM3-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 129..138 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 139..160 FT /note="Helical; Name=TM4-1" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 161..184 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 185..205 FT /note="Helical; Name=TM5-1" FT /evidence="ECO:0000255" FT TOPO_DOM 206..210 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 211..230 FT /note="Helical; Name=TM6-1" FT /evidence="ECO:0000255" FT TOPO_DOM 231..257 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 258..282 FT /note="Helical; Name=TM1-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 283..309 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 310..332 FT /note="Helical; Name=TM2-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 333..338 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 339..360 FT /note="Helical; Name=TM3-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 361..375 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 376..396 FT /note="Helical; Name=TM4-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 397..416 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 417..440 FT /note="Helical; Name=TM5-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 441..442 FT /note="Lumenal" FT /evidence="ECO:0000305" FT TRANSMEM 443..469 FT /note="Helical; Name=TM6-2" FT /evidence="ECO:0000305|PubMed:32228865, FT ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, FT ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC" FT TOPO_DOM 470..504 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:26317472" FT REGION 1..27 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 58..63 FT /note="Short helix H1-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 65..71 FT /note="Short helix H2-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 288..296 FT /note="Short helix H1-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 298..304 FT /note="Short helix H2-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT REGION 483..504 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 35..41 FT /note="RxxxFSD motif 1" FT /evidence="ECO:0000269|PubMed:26317472" FT MOTIF 260..266 FT /note="RxxxFSD motif 2" FT /evidence="ECO:0000305|PubMed:26317472" FT SITE 46 FT /note="Hydrophobic filter residue 1-1" FT /evidence="ECO:0000269|PubMed:28723891" FT SITE 50 FT /note="Hydrophobic filter residue 2-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT SITE 53 FT /note="Hydrophobic filter residue 3-1" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT SITE 271 FT /note="Hydrophobic filter residue 1-2" FT /evidence="ECO:0000269|PubMed:28723891" FT SITE 275 FT /note="Hydrophobic filter residue 2-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT SITE 278 FT /note="Hydrophobic filter residue 3-2" FT /evidence="ECO:0000250|UniProtKB:K9UJK2" FT MOD_RES 6 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18691976" FT VAR_SEQ 1..116 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_024213" FT VARIANT 65 FT /note="Q -> P (associated with decreased risk for Parkinson FT disease; gain-of-function variant; does not affect FT lysosomal localization; dbSNP:rs34884217)" FT /evidence="ECO:0000269|PubMed:31658403, FT ECO:0000269|PubMed:33505021" FT /id="VAR_053873" FT VARIANT 393 FT /note="M -> T (associated with increased risk for Parkinson FT disease; reduced potassium channel activity; does not FT affect lysosomal localization; dbSNP:rs34311866)" FT /evidence="ECO:0000269|PubMed:31261387, FT ECO:0000269|PubMed:31658403, ECO:0000269|PubMed:33505021" FT /id="VAR_053874" FT MUTAGEN 35 FT /note="R->A: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 38 FT /note="S->A: Does not affect proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 39 FT /note="F->V: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 40 FT /note="S->A: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 41 FT /note="D->A: Abolished proton permeability without altering FT potassium permeability." FT /evidence="ECO:0000269|PubMed:35750034" FT MUTAGEN 41 FT /note="D->E,N: Impaired potassium channel activity." FT /evidence="ECO:0000269|PubMed:26317472" FT MUTAGEN 45..49 FT /note="SIIAT->AIIAA: Decreased selectivity for potassium FT ion; when associated with A-274." FT /evidence="ECO:0000269|PubMed:32267231" FT MUTAGEN 45 FT /note="S->A: Reduced potassium channel activity without FT altering proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573, FT ECO:0000269|PubMed:35750034" FT MUTAGEN 45 FT /note="S->T: Decreased selectivity for potassium ion." FT /evidence="ECO:0000269|PubMed:32228865" FT MUTAGEN 46 FT /note="I->A,V: Decreased channel activity." FT /evidence="ECO:0000269|PubMed:35608336" FT MUTAGEN 46 FT /note="I->M: Abolished proton and potassium channel FT activity; when associated with M-271." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 46 FT /note="I->N: Impaired selectivity; can conduct both K(+) FT and Na(+); when associated with N-271." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 49 FT /note="T->A: Decreased selectivity for potassium ion." FT /evidence="ECO:0000269|PubMed:32267231" FT MUTAGEN 49 FT /note="T->V: Abolished potassium channel activity and FT decreased proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 50 FT /note="V->A: Does not affect selectivity; when associated FT with A-275." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 53 FT /note="L->A: Does not affect selectivity; when associated FT with A-278." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 241 FT /note="S->A: Reduced channel activation, probably caused by FT decreased interaction with AKT1; when associated with FT A-338." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 271 FT /note="I->A,V: Decreased channel activity." FT /evidence="ECO:0000269|PubMed:35608336" FT MUTAGEN 271 FT /note="I->N: Impaired selectivity; can conduct both K(+) FT and Na(+); when associated with N-46." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 271 FT /note="I->W: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 274 FT /note="T->A: Decreased selectivity for potassium ion. FT Abolished proton and potassium channel activity. Decreased FT selectivity for potassium ion; when associated with FT 45-A--A-49." FT /evidence="ECO:0000269|PubMed:32267231, FT ECO:0000269|PubMed:35333573" FT MUTAGEN 274 FT /note="T->V: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 274 FT /note="T->V: Decreased selectivity for potassium ion." FT /evidence="ECO:0000269|PubMed:32228865" FT MUTAGEN 275 FT /note="L->A: Does not affect selectivity; when associated FT with A-50." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 278 FT /note="L->A: Does not affect selectivity; when associated FT with A-53." FT /evidence="ECO:0000269|PubMed:28723891" FT MUTAGEN 279 FT /note="D->A: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 279 FT /note="D->N: Abolished potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 283 FT /note="D->A: Abolished proton and potassium channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 283 FT /note="D->N: Abolished potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 309 FT /note="R->A,Q: Reduced potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 327 FT /note="H->A: Reduced potassium and proton channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 328 FT /note="H->A: Reduced potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 338 FT /note="T->A: Reduced channel activation, probably caused by FT decreased interaction with AKT1; when associated with FT A-241." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 345 FT /note="N->L: Reduced potassium channel activity without FT affecting proton channel activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 360 FT /note="Q->L: Increased potassium and proton channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT MUTAGEN 393 FT /note="M->I: Does not affect potassium channel activity." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 393 FT /note="M->W: Reduced potassium channel activity." FT /evidence="ECO:0000269|PubMed:33505021" FT MUTAGEN 395 FT /note="T->W: Abolished interaction with LAMP1 and FT subsequent inhibition." FT /evidence="ECO:0000269|PubMed:37390818" FT MUTAGEN 449 FT /note="H->A: Increased potassium and proton channel FT activity." FT /evidence="ECO:0000269|PubMed:35333573" FT HELIX 34..48 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 49..52 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 53..56 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 64..66 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 67..101 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 107..120 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 123..132 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 134..136 FT /evidence="ECO:0007829|PDB:6WCA" FT HELIX 138..163 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 165..167 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 170..172 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 175..177 FT /evidence="ECO:0007829|PDB:6W8N" FT HELIX 181..204 FT /evidence="ECO:0007829|PDB:6W8N" FT TURN 208..211 FT /evidence="ECO:0007829|PDB:7LF6" FT HELIX 212..223 FT /evidence="ECO:0007829|PDB:6W8N" FT HELIX 224..227 FT /evidence="ECO:0007829|PDB:6W8O" FT STRAND 254..256 FT /evidence="ECO:0007829|PDB:8FYF" FT HELIX 258..283 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 290..293 FT /evidence="ECO:0007829|PDB:7UNL" FT TURN 294..297 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 299..304 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 307..331 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 333..335 FT /evidence="ECO:0007829|PDB:6WC9" FT HELIX 339..352 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 355..361 FT /evidence="ECO:0007829|PDB:7UNL" FT TURN 364..367 FT /evidence="ECO:0007829|PDB:7UNM" FT HELIX 369..398 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 401..404 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 407..409 FT /evidence="ECO:0007829|PDB:7UNL" FT STRAND 413..415 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 416..439 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 441..460 FT /evidence="ECO:0007829|PDB:7UNL" FT HELIX 462..475 FT /evidence="ECO:0007829|PDB:7UNL" SQ SEQUENCE 504 AA; 55615 MW; 7FEE4C22CA248094 CRC64; MSQPRTPEQA LDTPGDCPPG RRDEDAGEGI QCSQRMLSFS DALLSIIATV MILPVTHTEI SPEQQFDRSV QRLLATRIAV YLMTFLIVTV AWAAHTRLFQ VVGKTDDTLA LLNLACMMTI TFLPYTFSLM VTFPDVPLGI FLFCVCVIAI GVVQALIVGY AFHFPHLLSP QIQRSAHRAL YRRHVLGIVL QGPALCFAAA IFSLFFVPLS YLLMVTVILL PYVSKVTGWC RDRLLGHREP SAHPVEVFSF DLHEPLSKER VEAFSDGVYA IVATLLILDI CEDNVPDPKD VKERFSGSLV AALSATGPRF LAYFGSFATV GLLWFAHHSL FLHVRKATRA MGLLNTLSLA FVGGLPLAYQ QTSAFARQPR DELERVRVSC TIIFLASIFQ LAMWTTALLH QAETLQPSVW FGGREHVLMF AKLALYPCAS LLAFASTCLL SRFSVGIFHL MQIAVPCAFL LLRLLVGLAL ATLRVLRGLA RPEHPPPAPT GQDDPQSQLL PAPC //