TMEM175
entrez
84286
canonical
uniprot
Q9BSA9
canonical
ensembl
ENSG00000127419
resolver
ensp
ENSP00000264771
resolver
ensp
ENSP00000423669
resolver
ensp
ENSP00000427039
resolver
ensp
ENSP00000485461
resolver
ensp
ENSP00000574742
resolver
ensp
ENSP00000791091
resolver
enst
ENST00000508204
resolver
genesymbol
TMEM175
resolver
hgnc
HGNC:28709
resolver
uniprot
A0A9K3Y7F1
resolver
uniprot
D3DVN4
resolver
uniprot
D3DVN6
resolver
uniprot
F6UWG6
resolver
uniprot
Q8ND13
resolver
uniprot_entry
F6UWG6_HUMAN
resolver
uniprot_entry
TM175_HUMAN
resolver
uniprot_sec
A0A9K3Y7F1
resolver
uniprot_sec
D3DVN4
resolver
uniprot_sec
D3DVN6
resolver
uniprot_sec
Q8ND13
resolver
activity_regulation
ACTIVITY REGULATION: 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). {ECO:0000269|PubMed:33505021, ECO:0000269|PubMed:35750034, ECO:0000269|PubMed:37390818}.
uniprot
proteins
amino_acid_sequence
MSQPRTPEQALDTPGDCPPGRRDEDAGEGIQCSQRMLSFSDALLSIIATVMILPVTHTEISPEQQFDRSVQRLLATRIAVYLMTFLIVTVAWAAHTRLFQVVGKTDDTLALLNLACMMTITFLPYTFSLMVTFPDVPLGIFLFCVCVIAIGVVQALIVGYAFHFPHLLSPQIQRSAHRALYRRHVLGIVLQGPALCFAAAIFSLFFVPLSYLLMVTVILLPYVSKVTGWCRDRLLGHREPSAHPVEVFSFDLHEPLSKERVEAFSDGVYAIVATLLILDICEDNVPDPKDVKERFSGSLVAALSATGPRFLAYFGSFATVGLLWFAHHSLFLHVRKATRAMGLLNTLSLAFVGGLPLAYQQTSAFARQPRDELERVRVSCTIIFLASIFQLAMWTTALLHQAETLQPSVWFGGREHVLMFAKLALYPCASLLAFASTCLLSRFSVGIFHLMQIAVPCAFLLLRLLVGLALATLRVLRGLARPEHPPPAPTGQDDPQSQLLPAPC
uniprot
proteins
disease_involvement
DISEASE: Parkinson disease (PARK) [MIM:168600]: 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. {ECO:0000269|PubMed:28193887, ECO:0000269|PubMed:31261387, ECO:0000269|PubMed:31658403, ECO:0000269|PubMed:33505021}. Note=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). {ECO:0000269|PubMed:28193887}.
uniprot
proteins
function
FUNCTION: 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). {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:28723891, ECO:0000269|PubMed:32228865, ECO:0000269|PubMed:32267231, ECO:0000269|PubMed:33505021, ECO:0000269|PubMed:35333573, ECO:0000269|PubMed:35750034, ECO:0000269|PubMed:37390818}.
uniprot
proteins
mass_dalton
55615
uniprot
proteins
mutagenesis
MUTAGEN 35; /note="R->A: Impaired potassium channel activity."; /evidence="ECO:0000269|PubMed:26317472"; MUTAGEN 38; /note="S->A: Does not affect proton and potassium channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 39; /note="F->V: Impaired potassium channel activity."; /evidence="ECO:0000269|PubMed:26317472"; MUTAGEN 40; /note="S->A: Impaired potassium channel activity."; /evidence="ECO:0000269|PubMed:26317472"; MUTAGEN 41; /note="D->A: Abolished proton permeability without altering potassium permeability."; /evidence="ECO:0000269|PubMed:35750034"; MUTAGEN 41; /note="D->E,N: Impaired potassium channel activity."; /evidence="ECO:0000269|PubMed:26317472"; MUTAGEN 45..49; /note="SIIAT->AIIAA: Decreased selectivity for potassium ion; when associated with A-274."; /evidence="ECO:0000269|PubMed:32267231"; MUTAGEN 45; /note="S->A: Reduced potassium channel activity without altering proton channel activity."; /evidence="ECO:0000269|PubMed:35333573, ECO:0000269|PubMed:35750034"; MUTAGEN 45; /note="S->T: Decreased selectivity for potassium ion."; /evidence="ECO:0000269|PubMed:32228865"; MUTAGEN 46; /note="I->A,V: Decreased channel activity."; /evidence="ECO:0000269|PubMed:35608336"; MUTAGEN 46; /note="I->M: Abolished proton and potassium channel activity; when associated with M-271."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 46; /note="I->N: Impaired selectivity; can conduct both K(+) and Na(+); when associated with N-271."; /evidence="ECO:0000269|PubMed:28723891"; MUTAGEN 49; /note="T->A: Decreased selectivity for potassium ion."; /evidence="ECO:0000269|PubMed:32267231"; MUTAGEN 49; /note="T->V: Abolished potassium channel activity and decreased proton channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 50; /note="V->A: Does not affect selectivity; when associated with A-275."; /evidence="ECO:0000269|PubMed:28723891"; MUTAGEN 53; /note="L->A: Does not affect selectivity; when associated with A-278."; /evidence="ECO:0000269|PubMed:28723891"; MUTAGEN 241; /note="S->A: Reduced channel activation, probably caused by decreased interaction with AKT1; when associated with A-338."; /evidence="ECO:0000269|PubMed:33505021"; MUTAGEN 271; /note="I->A,V: Decreased channel activity."; /evidence="ECO:0000269|PubMed:35608336"; MUTAGEN 271; /note="I->N: Impaired selectivity; can conduct both K(+) and Na(+); when associated with N-46."; /evidence="ECO:0000269|PubMed:28723891"; MUTAGEN 271; /note="I->W: Abolished proton and potassium channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 274; /note="T->A: Decreased selectivity for potassium ion. Abolished proton and potassium channel activity. Decreased selectivity for potassium ion; when associated with 45-A--A-49."; /evidence="ECO:0000269|PubMed:32267231, ECO:0000269|PubMed:35333573"; MUTAGEN 274; /note="T->V: Abolished proton and potassium channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 274; /note="T->V: Decreased selectivity for potassium ion."; /evidence="ECO:0000269|PubMed:32228865"; MUTAGEN 275; /note="L->A: Does not affect selectivity; when associated with A-50."; /evidence="ECO:0000269|PubMed:28723891"; MUTAGEN 278; /note="L->A: Does not affect selectivity; when associated with A-53."; /evidence="ECO:0000269|PubMed:28723891"; MUTAGEN 279; /note="D->A: Abolished proton and potassium channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 279; /note="D->N: Abolished potassium channel activity without affecting proton channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 283; /note="D->A: Abolished proton and potassium channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 283; /note="D->N: Abolished potassium channel activity without affecting proton channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 309; /note="R->A,Q: Reduced potassium channel activity without affecting proton channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 327; /note="H->A: Reduced potassium and proton channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 328; /note="H->A: Reduced potassium channel activity without affecting proton channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 338; /note="T->A: Reduced channel activation, probably caused by decreased interaction with AKT1; when associated with A-241."; /evidence="ECO:0000269|PubMed:33505021"; MUTAGEN 345; /note="N->L: Reduced potassium channel activity without affecting proton channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 360; /note="Q->L: Increased potassium and proton channel activity."; /evidence="ECO:0000269|PubMed:35333573"; MUTAGEN 393; /note="M->I: Does not affect potassium channel activity."; /evidence="ECO:0000269|PubMed:33505021"; MUTAGEN 393; /note="M->W: Reduced potassium channel activity."; /evidence="ECO:0000269|PubMed:33505021"; MUTAGEN 395; /note="T->W: Abolished interaction with LAMP1 and subsequent inhibition."; /evidence="ECO:0000269|PubMed:37390818"; MUTAGEN 449; /note="H->A: Increased potassium and proton channel activity."; /evidence="ECO:0000269|PubMed:35333573
uniprot
proteins
protein_family
TMEM175 family
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
17974005
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
26317472
uniprot
proteins
pubmed
28193887
uniprot
proteins
pubmed
28723891
uniprot
proteins
pubmed
31261387
uniprot
proteins
pubmed
31658403
uniprot
proteins
pubmed
32228865
uniprot
proteins
pubmed
32267231
uniprot
proteins
pubmed
33505021
uniprot
proteins
pubmed
35333573
uniprot
proteins
pubmed
35608336
uniprot
proteins
pubmed
35750034
uniprot
proteins
pubmed
37390818
uniprot
proteins
sequence_length
504
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Endosome membrane {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:32228865}; Multi-pass membrane protein {ECO:0000269|PubMed:32228865}. Lysosome membrane {ECO:0000269|PubMed:26317472, ECO:0000269|PubMed:31261387, ECO:0000269|PubMed:31658403, ECO:0000269|PubMed:32228865}; Multi-pass membrane protein {ECO:0000269|PubMed:32228865}.
uniprot
proteins
transmembrane_region
TRANSMEM 34..56; /note="Helical; Name=TM1-1"; /evidence="ECO:0000305|PubMed:32228865, ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC"; TRANSMEM 78..100; /note="Helical; Name=TM2-1"; /evidence="ECO:0000305|PubMed:32228865, ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC"; TRANSMEM 107..128; /note="Helical; Name=TM3-1"; /evidence="ECO:0000305|PubMed:32228865, ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC"; TRANSMEM 139..160; /note="Helical; Name=TM4-1"; /evidence="ECO:0000305|PubMed:32228865, ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC"; TRANSMEM 185..205; /note="Helical; Name=TM5-1"; /evidence="ECO:0000255"; TRANSMEM 211..230; /note="Helical; Name=TM6-1"; /evidence="ECO:0000255"; TRANSMEM 258..282; /note="Helical; Name=TM1-2"; /evidence="ECO:0000305|PubMed:32228865, ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC"; TRANSMEM 310..332; /note="Helical; Name=TM2-2"; /evidence="ECO:0000305|PubMed:32228865, ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC"; TRANSMEM 339..360; /note="Helical; Name=TM3-2"; /evidence="ECO:0000305|PubMed:32228865, ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC"; TRANSMEM 376..396; /note="Helical; Name=TM4-2"; /evidence="ECO:0000305|PubMed:32228865, ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC"; TRANSMEM 417..440; /note="Helical; Name=TM5-2"; /evidence="ECO:0000305|PubMed:32228865, ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC"; TRANSMEM 443..469; /note="Helical; Name=TM6-2"; /evidence="ECO:0000305|PubMed:32228865, ECO:0007744|PDB:6WC9, ECO:0007744|PDB:6WCA, ECO:0007744|PDB:6WCB, ECO:0007744|PDB:6WCC
uniprot
proteins