MCOLN1
entrez
57192
canonical
uniprot
Q9GZU1
canonical
ensembl
ENSG00000090674
resolver
ensp
ENSP00000264079
resolver
enst
ENST00000264079
resolver
genesymbol
MCOLN1
resolver
genesymbol_syn
ML4
resolver
genesymbol_syn
TRPML1
resolver
hgnc
HGNC:13356
resolver
uniprot
D6W647
resolver
uniprot
Q7Z4F7
resolver
uniprot
Q9H292
resolver
uniprot
Q9H4B3
resolver
uniprot
Q9H4B5
resolver
uniprot_entry
MCLN1_HUMAN
resolver
uniprot_sec
D6W647
resolver
uniprot_sec
Q7Z4F7
resolver
uniprot_sec
Q9H292
resolver
uniprot_sec
Q9H4B3
resolver
uniprot_sec
Q9H4B5
resolver
activity_regulation
ACTIVITY REGULATION: Channel activity is controlled by multiple regulatory mechanisms in different subcellular compartments. Channel function is transiently modulated by changes in Ca(2+) in a pH-dependent manner; pH changes modify the aggregation state of unitary channels; a negative cooperativity between extracellular/lumenal Ca(2+) and H(+) is suggested (PubMed:12459486, PubMed:28112729). Regulated by phosphoinositides in a compartment-specific manner: in lysosomes activated by PtdIns(3,5)P2 (Phosphatidylinositol 3,5-bisphosphate) and at the plasma membrane inhibited by PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) (PubMed:22733759, PubMed:29019983). {ECO:0000269|PubMed:12459486, ECO:0000269|PubMed:22733759, ECO:0000269|PubMed:28112729, ECO:0000269|PubMed:29019983}.
uniprot
proteins
amino_acid_sequence
MTAPAGPRGSETERLLTPNPGYGTQAGPSPAPPTPPEEEDLRRRLKYFFMSPCDKFRAKGRKPCKLMLQVVKILVVTVQLILFGLSNQLAVTFREENTIAFRHLFLLGYSDGADDTFAAYTREQLYQAIFHAVDQYLALPDVSLGRYAYVRGGGDPWTNGSGLALCQRYYHRGHVDPANDTFDIDPMVVTDCIQVDPPERPPPPPSDDLTLLESSSSYKNLTLKFHKLVNVTIHFRLKTINLQSLINNEIPDCYTFSVLITFDNKAHSGRIPISLETQAHIQECKHPSVFQHGDNSFRLLFDVVVILTCSLSFLLCARSLLRGFLLQNEFVGFMWRQRGRVISLWERLEFVNGWYILLVTSDVLTISGTIMKIGIEAKNLASYDVCSILLGTSTLLVWVGVIRYLTFFHNYNILIATLRVALPSVMRFCCCVAVIYLGYCFCGWIVLGPYHVKFRSLSMVSECLFSLINGDDMFVTFAAMQAQQGRSSLVWLFSQLYLYSFISLFIYMVLSLFIALITGAYDTIKHPGGAGAEESELQAYIAQCQDSPTSGKFRRGSGSACSLLCCCGRDPSEEHSLLVN
uniprot
proteins
disease_involvement
DISEASE: Mucolipidosis 4 (ML4) [MIM:252650]: An autosomal recessive lysosomal storage disorder characterized by severe psychomotor retardation and ophthalmologic abnormalities, including corneal opacity, retinal degeneration and strabismus. Storage bodies of lipids and water-soluble substances are seen by electron microscopy in almost every cell type of the patients. Most patients are unable to speak or walk independently and reach a maximal developmental level of 1-2 years. All patients have constitutive achlorhydia associated with a secondary elevation of serum gastrin levels. {ECO:0000269|PubMed:10973263, ECO:0000269|PubMed:11013137, ECO:0000269|PubMed:11030752, ECO:0000269|PubMed:11317355, ECO:0000269|PubMed:12182165, ECO:0000269|PubMed:14749347, ECO:0000269|PubMed:15178326, ECO:0000269|PubMed:15523648, ECO:0000269|PubMed:16978393, ECO:0000269|PubMed:18794901, ECO:0000269|PubMed:20159435, ECO:0000269|PubMed:21256127, ECO:0000269|PubMed:28112729}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Corneal dystrophy, Lisch epithelial (LECD) [MIM:620763]: An autosomal dominant corneal dystrophy characterized by gray, band-shaped and feathery opacities in the cornea, that sometimes appear in whorled patterns. The opaque bands consist of clear, densely crowded, intra-epithelial blisters. Vision may be impaired if the bands involve the central cornea. {ECO:0000269|PubMed:37972748}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
function
FUNCTION: Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis (PubMed:11013137, PubMed:12459486, PubMed:14749347, PubMed:15336987, PubMed:18794901, PubMed:25720963, PubMed:27623384, PubMed:29019983). Acts as a Ca(2+)-permeable cation channel with inwardly rectifying activity (PubMed:25720963, PubMed:29019983). Proposed to play a major role in Ca(2+) release from late endosome and lysosome vesicles to the cytoplasm, which is important for many lysosome-dependent cellular events, including the fusion and trafficking of these organelles, exocytosis and autophagy (PubMed:11013137, PubMed:12459486, PubMed:14749347, PubMed:15336987, PubMed:25720963, PubMed:27623384, PubMed:29019983). Required for efficient uptake of large particles in macrophages in which Ca(2+) release from the lysosomes triggers lysosomal exocytosis. May also play a role in phagosome-lysosome fusion (By similarity). Involved in lactosylceramide trafficking indicative for a role in the regulation of late endocytic membrane fusion/fission events (PubMed:16978393). By mediating lysosomal Ca(2+) release is involved in regulation of mTORC1 signaling and in mTOR/TFEB-dependent lysosomal adaptation to environmental cues such as nutrient levels (PubMed:25720963, PubMed:25733853, PubMed:27787197). Seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS-induced TFEB activation and autophagy (PubMed:27357649). Also functions as a Fe(2+) permeable channel in late endosomes and lysosomes (PubMed:18794901). Also permeable to Mg(2+), Na(+), K(+) and Cs(+) (By similarity). Proposed to play a role in zinc homeostasis probably implicating its association with TMEM163 (PubMed:25130899) In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells (By similarity). {ECO:0000250|UniProtKB:Q99J21, ECO:0000269|PubMed:12459486, ECO:0000269|PubMed:14749347, ECO:0000269|PubMed:15336987, ECO:0000269|PubMed:16978393, ECO:0000269|PubMed:18794901, ECO:0000269|PubMed:25130899, ECO:0000269|PubMed:25720963, ECO:0000269|PubMed:25733853, ECO:0000269|PubMed:27357649, ECO:0000269|PubMed:27623384, ECO:0000269|PubMed:27787197, ECO:0000269|PubMed:29019983, ECO:0000305|PubMed:11013137}.; FUNCTION: May contribute to cellular lipase activity within the late endosomal pathway or at the cell surface which may be involved in processes of membrane reshaping and vesiculation, especially the growth of tubular structures. However, it is not known, whether it conveys the enzymatic activity directly, or merely facilitates the activity of an associated phospholipase. {ECO:0000305|PubMed:21256127}.
uniprot
proteins
mass_dalton
65022
uniprot
proteins
mutagenesis
MUTAGEN 15..16; /note="LL->AA: No effect on localization to lysosomes."; /evidence="ECO:0000269|PubMed:16497227"; MUTAGEN 15; /note="L->A: Abolishes localization to lysosomes and leads to expression at the cell membrane; when associated with A-577."; /evidence="ECO:0000269|PubMed:16497227, ECO:0000269|PubMed:29019983"; MUTAGEN 42..44; /note="RRR->AAA: Reduces PtdIns(4,5)P2 sensitivity."; /evidence="ECO:0000269|PubMed:22733759"; MUTAGEN 44..46; /note="RLK->AAA: Abolishes interaction with PDCD6 and decreases formation of aberrant endosomes upon overexpression."; /evidence="ECO:0000269|PubMed:19864416"; MUTAGEN 44; /note="R->A: Abolishes interaction with PDCD6."; /evidence="ECO:0000269|PubMed:19864416"; MUTAGEN 45; /note="L->A: Abolishes interaction with PDCD6."; /evidence="ECO:0000269|PubMed:19864416"; MUTAGEN 47..49; /note="YFF->AAA: Abolishes interaction with PDCD6."; /evidence="ECO:0000269|PubMed:19864416"; MUTAGEN 61..62; /note="RK->AA: Reduces PtdIns(3,5)P2 sensitivity."; /evidence="ECO:0000269|PubMed:22733759"; MUTAGEN 109; /note="Y->G: Abolishes formation and extrusion of tubulo-vesicular structures and decreases lysosomal exocytosis when overexpressed."; /evidence="ECO:0000269|PubMed:21256127"; MUTAGEN 110; /note="S->C: Modulates ion conduction; when associated with C-112 and C-113."; /evidence="ECO:0000269|PubMed:28112729"; MUTAGEN 111; /note="D->Q: Modulates inhibition by Ca(2+) at different pH levels but does not abolish channel inward rectification; when associated with Q-114 and Q-115."; /evidence="ECO:0000269|PubMed:28112729"; MUTAGEN 112; /note="G->C: Modulates ion conduction; when associated with C-110 and C-113."; /evidence="ECO:0000269|PubMed:28112729"; MUTAGEN 113; /note="A->C: Modulates ion conduction; when associated with C-110 and C-112."; /evidence="ECO:0000269|PubMed:28112729"; MUTAGEN 114; /note="D->Q: Modulates inhibition by Ca(2+) at different pH levels but does not abolish channel inward rectification; when associated with Q-111 and Q-115."; /evidence="ECO:0000269|PubMed:28112729"; MUTAGEN 115; /note="D->Q: Modulates inhibition by Ca(2+) at different pH levels but does not abolish channel inward rectification; when associated with Q-111 and Q-114."; /evidence="ECO:0000269|PubMed:28112729"; MUTAGEN 144; /note="L->K: Disrupts tetrameric assembly and abolishes lysosomal localization; when associated with S-146."; /evidence="ECO:0000269|PubMed:28112729"; MUTAGEN 146; /note="R->S: Disrupts tetrameric assembly and abolishes lysosomal localization; when associated with K-144."; /evidence="ECO:0000269|PubMed:28112729"; MUTAGEN 200; /note="R->H: Does not prevent proteolytic cleavage but changes cleavage pattern."; /evidence="ECO:0000269|PubMed:16257972"; MUTAGEN 432; /note="V->P: Mediates localization to the plasma membrane and strong inwardly rectifying current."; /evidence="ECO:0000269|PubMed:28112729"; MUTAGEN 471; /note="D->A: Fails to rescue defect of lactosylceramide traffic through the late endocytic pathway in ML4 patient cells."; /evidence="ECO:0000269|PubMed:16978393"; MUTAGEN 565..567; /note="CCC->AAA: Abolishes association with membranes."; /evidence="ECO:0000269|PubMed:16497227"; MUTAGEN 577..578; /note="LL->AA: No effect on localization to lysosomes."; /evidence="ECO:0000269|PubMed:16497227"; MUTAGEN 577; /note="L->A: Abolishes localization to lysosomes and leads to expression at the cell membrane; when associated with A-15."; /evidence="ECO:0000269|PubMed:16497227, ECO:0000269|PubMed:29019983
uniprot
proteins
post_translational_modification
PTM: Palmitoylated; involved in association with membranes. {ECO:0000269|PubMed:16497227}.; PTM: Phosphorylation by PKA inhibits channel activity. Dephosphorylation increases activity. {ECO:0000269|PubMed:17988215}.; PTM: Proteolytically cleaved probably involving multiple lysosomal proteases including cathepsin B; inhibits lysosomal channel activity (PubMed:16257972). {ECO:0000269|PubMed:16257972}.
uniprot
proteins
protein_family
MCOLN1 sub-subfamily
uniprot
proteins
protein_family
Polycystin subfamily
uniprot
proteins
protein_family
Transient receptor (TC 1.A.4) family
uniprot
proteins
pubmed
10973263
uniprot
proteins
pubmed
11013137
uniprot
proteins
pubmed
11030752
uniprot
proteins
pubmed
11317355
uniprot
proteins
pubmed
12182165
uniprot
proteins
pubmed
12459486
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
14749347
uniprot
proteins
pubmed
15178326
uniprot
proteins
pubmed
15336987
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15523648
uniprot
proteins
pubmed
16257972
uniprot
proteins
pubmed
16497227
uniprot
proteins
pubmed
16959974
uniprot
proteins
pubmed
16978393
uniprot
proteins
pubmed
17897319
uniprot
proteins
pubmed
17988215
uniprot
proteins
pubmed
18794901
uniprot
proteins
pubmed
19159218
uniprot
proteins
pubmed
19864416
uniprot
proteins
pubmed
19885840
uniprot
proteins
pubmed
20159435
uniprot
proteins
pubmed
21224396
uniprot
proteins
pubmed
21256127
uniprot
proteins
pubmed
22733759
uniprot
proteins
pubmed
25130899
uniprot
proteins
pubmed
25720963
uniprot
proteins
pubmed
25733853
uniprot
proteins
pubmed
27357649
uniprot
proteins
pubmed
27623384
uniprot
proteins
pubmed
27787197
uniprot
proteins
pubmed
28112729
uniprot
proteins
pubmed
29019983
uniprot
proteins
pubmed
37972748
uniprot
proteins
sequence_length
580
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Late endosome membrane {ECO:0000269|PubMed:15178326, ECO:0000269|PubMed:21224396}; Multi-pass membrane protein {ECO:0000269|PubMed:29019983}. Lysosome membrane {ECO:0000269|PubMed:12459486, ECO:0000269|PubMed:21224396, ECO:0000269|PubMed:25733853, ECO:0000305|PubMed:16497227, ECO:0000305|PubMed:16978393}; Multi-pass membrane protein {ECO:0000269|PubMed:29019983}. Cytoplasmic vesicle membrane {ECO:0000269|PubMed:12459486}; Multi-pass membrane protein {ECO:0000269|PubMed:29019983}. Cell projection, phagocytic cup {ECO:0000250|UniProtKB:Q99J21}. Cytoplasmic vesicle, phagosome membrane {ECO:0000250|UniProtKB:Q99J21}; Multi-pass membrane protein {ECO:0000269|PubMed:29019983}. Cell membrane {ECO:0000305|PubMed:29019983}; Multi-pass membrane protein {ECO:0000269|PubMed:29019983}. Note=Delivery from the trans-Golgi to lysosomes seems to occur mainly in a direct intracellular manner without intermediate delivery to the plasma membrane (PubMed:16497227). Under normal conditions, restricted to intracellular compartments so that only a very minor proportion is present at the cell membrane (PubMed:12459486, PubMed:18794901, PubMed:28112729, PubMed:29019983). {ECO:0000269|PubMed:12459486, ECO:0000269|PubMed:18794901, ECO:0000269|PubMed:28112729, ECO:0000269|PubMed:29019983, ECO:0000305|PubMed:16497227}.
uniprot
proteins
transmembrane_region
TRANSMEM 66..86; /note="Helical; Name=1"; /evidence="ECO:0000269|PubMed:29019983"; TRANSMEM 299..321; /note="Helical; Name=2"; /evidence="ECO:0000269|PubMed:29019983"; TRANSMEM 351..371; /note="Helical; Name=3"; /evidence="ECO:0000269|PubMed:29019983"; TRANSMEM 383..405; /note="Helical; Name=4"; /evidence="ECO:0000269|PubMed:29019983"; TRANSMEM 428..448; /note="Helical; Name=5"; /evidence="ECO:0000269|PubMed:29019983"; TRANSMEM 492..513; /note="Helical; Name=6"; /evidence="ECO:0000269|PubMed:29019983
uniprot
proteins