TM175_HUMAN
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 03-AUG-2022, entry version 132.
DE RecName: Full=Endosomal/lysosomal 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, 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, DOMAIN, SUBCELLULAR LOCATION, TOPOLOGY, TISSUE SPECIFICITY, AND
RP 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, SUBUNIT, DOMAIN, AND MUTAGENESIS OF ILE-46; VAL-50; LEU-53;
RP 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, AND MUTAGENESIS OF 45-SER--THR-49; THR-49 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, ACTIVITY REGULATION, INTERACTION WITH AKT1, IDENTIFICATION IN THE
RP LYSOK(GF) COMPLEX, INVOLVEMENT IN PARK, CHARACTERIZATION OF VARIANTS PRO-65
RP AND THR-393, AND MUTAGENESIS OF 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] {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, SUBCELLULAR
RP LOCATION, SUBUNIT, DOMAIN, AND MUTAGENESIS OF SER-45 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).
CC -!- FUNCTION: Organelle-specific potassium channel specifically responsible
CC for potassium conductance in endosomes and lysosomes (PubMed:26317472,
CC PubMed:28723891, PubMed:32267231, PubMed:33505021, PubMed:32228865).
CC Forms a potassium-permeable leak-like channel, which regulates lumenal
CC pH stability and is required for autophagosome-lysosome fusion
CC (PubMed:26317472, PubMed:28723891, PubMed:32267231, PubMed:33505021,
CC PubMed:32228865). Constitutes the major lysosomal potassium channel
CC (PubMed:26317472, PubMed:28723891). Constitutes the pore-forming
CC subunit of the lysoK(GF) complex, a complex activated by extracellular
CC growth factors (PubMed:33505021). The lysoK(GF) complex is composed of
CC TMEM175 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:0000269|PubMed:26317472,
CC ECO:0000269|PubMed:28723891, ECO:0000269|PubMed:32228865,
CC ECO:0000269|PubMed:32267231, 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 (PubMed:33505021). Activation
CC by AKT is independent of AKT serine/threonine-protein kinase activity
CC (PubMed:33505021). {ECO:0000269|PubMed:33505021}.
CC -!- SUBUNIT: Homodimer (Probable) (PubMed:32228865). Interacts with AKT
CC (AKT1, AKT2 or AKT3); leading to formation of the lysoK(GF) complex,
CC which activates the channel (PubMed:33505021).
CC {ECO:0000269|PubMed:32228865, ECO:0000269|PubMed:33505021,
CC 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}.
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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. [Q9BSA9-2]
DR RefSeq; XP_016864190.1; XM_017008701.1. [Q9BSA9-1]
DR RefSeq; XP_016864194.1; XM_017008705.1. [Q9BSA9-2]
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 PDBsum; 6W8N; -.
DR PDBsum; 6W8O; -.
DR PDBsum; 6W8P; -.
DR PDBsum; 6WC9; -.
DR PDBsum; 6WCA; -.
DR PDBsum; 6WCB; -.
DR PDBsum; 6WCC; -.
DR PDBsum; 7LF6; -.
DR AlphaFoldDB; Q9BSA9; -.
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 BioMuta; TMEM175; -.
DR DMDM; 74732981; -.
DR EPD; Q9BSA9; -.
DR jPOST; Q9BSA9; -.
DR MassIVE; Q9BSA9; -.
DR MaxQB; Q9BSA9; -.
DR PaxDb; Q9BSA9; -.
DR PeptideAtlas; Q9BSA9; -.
DR PRIDE; Q9BSA9; -.
DR ProteomicsDB; 78871; -. [Q9BSA9-1]
DR ProteomicsDB; 78872; -. [Q9BSA9-2]
DR Antibodypedia; 8167; 63 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 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; 894975at2759; -.
DR PhylomeDB; Q9BSA9; -.
DR TreeFam; TF328838; -.
DR PathwayCommons; Q9BSA9; -.
DR SignaLink; Q9BSA9; -.
DR BioGRID-ORCS; 84286; 14 hits in 1075 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 155 other tissues.
DR ExpressionAtlas; Q9BSA9; baseline and differential.
DR Genevisible; Q9BSA9; HS.
DR GO; GO:0005768; C:endosome; IDA:UniProtKB.
DR GO; GO:0031303; C:integral component of endosome membrane; IDA:UniProtKB.
DR GO; GO:1905103; C:integral component of lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; 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: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:0035751; P:regulation of lysosomal lumen pH; IEA:Ensembl.
DR InterPro; IPR010617; TMEM175.
DR Pfam; PF06736; TMEM175; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Endosome; Ion channel; Ion transport;
KW Lysosome; Membrane; Neurodegeneration; Parkinson disease; Parkinsonism;
KW Phosphoprotein; Potassium; Potassium channel; Potassium transport;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..504
FT /note="Endosomal/lysosomal potassium 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:0000305"
FT MUTAGEN 39
FT /note="F->V: Impaired potassium channel activity."
FT /evidence="ECO:0000305"
FT MUTAGEN 40
FT /note="S->A: Impaired potassium channel activity."
FT /evidence="ECO:0000305"
FT MUTAGEN 41
FT /note="D->A,E,N: Impaired potassium channel activity."
FT /evidence="ECO:0000305"
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->T: Decreased selectivity for potassium ion."
FT /evidence="ECO:0000269|PubMed:32228865"
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 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 A-
FT 338."
FT /evidence="ECO:0000269|PubMed:33505021"
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 274
FT /note="T->A: Decreased selectivity for potassium ion.
FT Decreased selectivity for potassium ion; when associated
FT with 45-A--A-49."
FT /evidence="ECO:0000269|PubMed:32267231"
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 338
FT /note="T->A: Reduced channel activation, probably caused by
FT decreased interaction with AKT1; when associated with A-
FT 241."
FT /evidence="ECO:0000269|PubMed:33505021"
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 HELIX 34..48
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 50..52
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 53..56
FT /evidence="ECO:0007829|PDB:6WC9"
FT STRAND 63..65
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 67..101
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 107..120
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 123..132
FT /evidence="ECO:0007829|PDB:6WC9"
FT STRAND 134..136
FT /evidence="ECO:0007829|PDB:6WCA"
FT HELIX 138..163
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 165..167
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 170..172
FT /evidence="ECO:0007829|PDB:6WC9"
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 HELIX 258..283
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 288..294
FT /evidence="ECO:0007829|PDB:6WC9"
FT STRAND 295..297
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 299..305
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 307..331
FT /evidence="ECO:0007829|PDB:6WC9"
FT STRAND 333..335
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 339..352
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 355..363
FT /evidence="ECO:0007829|PDB:6WC9"
FT TURN 364..366
FT /evidence="ECO:0007829|PDB:6WCA"
FT HELIX 369..398
FT /evidence="ECO:0007829|PDB:6WC9"
FT TURN 402..404
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 407..409
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 416..438
FT /evidence="ECO:0007829|PDB:6WC9"
FT STRAND 441..443
FT /evidence="ECO:0007829|PDB:6WCA"
FT HELIX 444..460
FT /evidence="ECO:0007829|PDB:6WC9"
FT HELIX 462..475
FT /evidence="ECO:0007829|PDB:6WC9"
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
