{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q9BSA9","secondaryAccessions":["D3DVN4","Q8ND13"],"uniProtkbId":"TM175_HUMAN","entryAudit":{"firstPublicDate":"2007-04-03","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2001-06-01","entryVersion":150,"sequenceVersion":1},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Endosomal/lysosomal proton channel TMEM175"}},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Potassium channel TMEM175"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"26317472"}],"value":"Transmembrane protein 175"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"26317472"},{"evidenceCode":"ECO:0000303","source":"PubMed","id":"28723891"},{"evidenceCode":"ECO:0000303","source":"PubMed","id":"32228865"}],"value":"hTMEM175"}]}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"26317472"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:28709"}],"value":"TMEM175"}}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26317472"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28723891"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32228865"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32267231"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33505021"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35333573"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35750034"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37390818"}],"value":"Proton-activated proton channel that catalyzes proton efflux from endosomes and lysosomes to maintain a steady-state pH (PubMed:35333573, PubMed:35750034, PubMed:37390818). Activated at low pH (under pH 4.6) by luminal side protons: selectively mediates lysosomal proton release from lysosomes, eliciting a proton leak that balances V-ATPase activity to maintain pH homeostasis (PubMed:35750034). Regulation of lumenal pH stability is required for autophagosome-lysosome fusion (PubMed:26317472, PubMed:32267231). Also acts as a potassium channel at higher pH, regulating potassium conductance in endosomes and lysosomes (PubMed:26317472, PubMed:28723891, PubMed:32228865, PubMed:32267231, PubMed:33505021). Constitutes the pore-forming subunit of the lysoK(GF) complex, a complex activated by extracellular growth factors (PubMed:33505021). The lysoK(GF) complex is composed of TMEM175 and AKT (AKT1, AKT2 or AKT3), a major target of growth factor receptors: in the complex, TMEM175 channel is opened by conformational changes by AKT, leading to its activation (PubMed:33505021). The lysoK(GF) complex is required to protect neurons against stress-induced damage (PubMed:33505021)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"H(+)(in) = H(+)(out)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:34979"},{"database":"ChEBI","id":"CHEBI:15378"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35750034"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37390818"}]}},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"K(+)(in) = K(+)(out)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:29463"},{"database":"ChEBI","id":"CHEBI:29103"}],"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26317472"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28723891"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32228865"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32267231"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33505021"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33505021"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35750034"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37390818"}],"value":"Active at low pH (under pH 4.6): proton channel activity is activated by luminal side protons (PubMed:35750034). Polyunsaturated fatty acids, such as arachidonic acid, also activate the channel activity (PubMed:35750034). Proton channel activity is directly inhibited by LAMP1 or LAMP2, facilitating lysosomal acidification (PubMed:37390818). Channel activity is activated following interaction with AKT (AKT1, AKT2 or AKT3): interaction promotes activation from closed to an open state (PubMed:33505021). Activation by AKT is independent of AKT serine/threonine-protein kinase activity (PubMed:33505021)"}],"commentType":"ACTIVITY REGULATION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32228865"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33505021"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35608336"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37390818"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"28723891"}],"value":"Homodimer (PubMed:28723891, PubMed:32228865, PubMed:35608336). Interacts with AKT (AKT1, AKT2 or AKT3); leading to formation of the lysoK(GF) complex, which activates the channel (PubMed:33505021). Interacts with LAMP1; inhibiting the proton channel activity of TMEM175 (PubMed:37390818). Interacts with LAMP2; inhibiting the proton channel activity of TMEM175 (PubMed:37390818)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26317472"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32228865"}],"value":"Endosome membrane","id":"SL-0100"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32228865"}],"value":"Multi-pass membrane protein","id":"SL-9909"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26317472"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31261387"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31658403"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32228865"}],"value":"Lysosome membrane","id":"SL-0157"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32228865"}],"value":"Multi-pass membrane protein","id":"SL-9909"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"isoformIds":["Q9BSA9-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"isoformIds":["Q9BSA9-2"],"sequenceIds":["VSP_024213"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26317472"}],"value":"Widely expressed"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28723891"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32228865"}],"value":"Composed of two modules of six transmembranes, forming a homodimer with a tetrameric architecture (PubMed:28723891, PubMed:32228865). The six transmembrane regions of each module are tightly packed within each subunit without undergoing domain swapping (PubMed:32228865). Forms a central ion-conduction pore lined by the side chains of the pore-lining helices (PubMed:32228865). Conserved isoleucine residues (Ile-46 in the first module and Ile-271 in the second module) in the center of the pore serve as the gate in the closed conformation (PubMed:32228865). In the widened channel in the open conformation, Ser-45 and Ile-46 in the first module (and Thr-274 and Ile-271 in the second module), establish a constriction essential for potassium selectivity (PubMed:32228865)"}],"commentType":"DOMAIN"},{"commentType":"DISEASE","disease":{"diseaseId":"Parkinson disease","diseaseAccession":"DI-02134","acronym":"PARK","description":"A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features.","diseaseCrossReference":{"database":"MIM","id":"168600"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28193887"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31261387"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31658403"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33505021"}]},"note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28193887"}],"value":"Disease susceptibility may be associated with variants affecting the gene represented in this entry. TMEM175 defects result in unstable lysosomal pH, leading to decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance by the lysosome and decreased mitochondrial respiration (PubMed:28193887)"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the TMEM175 family"}],"commentType":"SIMILARITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26317472"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35750034"}],"value":"A publication claims that potassium transport was initially measured with a luminal side pH above 7.0, which is non-physiological for lysosomal channels (PubMed:35750034). This statement is however incorrect as potassium transport was tested at lumenal pH of 5.5, which is considered physiological (PubMed:26317472)"}],"commentType":"CAUTION"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":504,"modifier":"EXACT"}},"description":"Endosomal/lysosomal proton channel TMEM175","featureId":"PRO_0000282588"},{"type":"Topological domain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":33,"modifier":"EXACT"}},"description":"Cytoplasmic","evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"26317472"}]},{"type":"Transmembrane","location":{"start":{"value":34,"modifier":"EXACT"},"end":{"value":56,"modifier":"EXACT"}},"description":"Helical; Name=TM1-1","evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"32228865"},{"evidenceCode":"ECO:0007744","source":"PDB","id":"6WC9"},{"evidenceCode":"ECO:0007744","source":"PDB","id":"6WCA"},{"evidenceCode":"ECO:0007744","source":"PDB","id":"6WCB"},{"evidenceCode":"ECO:0007744","source":"PDB","id":"6WCC"}]},{"type":"Topological domain","location":{"start":{"value":57,"modifier":"EXACT"},"end":{"value":77,"modifier":"EXACT"}},"description":"Lumenal","evidences":[{"evidenceCode":"ECO:0000305"}]},{"type":"Transmembrane","location":{"start":{"value":78,"modifier":"EXACT"},"end":{"value":100,"modifier":"EXACT"}},"description":"Helical; 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