| IED ID | IndEnz0005001138 |
| Enzyme Type ID | lipase001138 |
| Protein Name |
Mucolipin-1 Mucolipidin Transient receptor potential-mucolipin 1 TRPML1 |
| Gene Name | Mcoln1 Trpml1 |
| Organism | Mus musculus (Mouse) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Mus Mus Mus musculus (Mouse) |
| Enzyme Sequence | MATPAGRRASETERLLTPNPGYGTQVGTSPAPTTPTEEEDLRRRLKYFFMSPCDKFRAKGRKPCKLMLQVVKILVVTVQLILFGLSNQLVVTFREENTIAFRHLFLLGYSDGSDDTFAAYTQEQLYQAIFYAVDQYLILPEISLGRYAYVRGGGGPWANGSALALCQRYYHRGHVDPANDTFDIDPRVVTDCIQVDPPDRPPDIPSEDLDFLDGSASYKNLTLKFHKLINVTIHFQLKTINLQSLINNEIPDCYTFSILITFDNKAHSGRIPIRLETKTHIQECKHPSVSRHGDNSFRLLFDVVVILTCSLSFLLCARSLLRGFLLQNEFVVFMWRRRGREISLWERLEFVNGWYILLVTSDVLTISGTVMKIGIEAKNLASYDVCSILLGTSTLLVWVGVIRYLTFFHKYNILIATLRVALPSVMRFCCCVAVIYLGYCFCGWIVLGPYHVKFRSLSMVSECLFSLINGDDMFVTFAAMQAQQGHSSLVWLFSQLYLYSFISLFIYMVLSLFIALITGAYDTIKHPGGTGTEKSELQAYIEQCQDSPTSGKFRRGSGSACSLFCCCGRDSPEDHSLLVN |
| Enzyme Length | 580 |
| Uniprot Accession Number | Q99J21 |
| Absorption | |
| Active Site | |
| Activity Regulation | ACTIVITY REGULATION: Channel activity is controlled by multiple regulatory mechanisms in different subcellular compartments (By similarity). Channel function is transiently modulated by changes in Ca(2+), and inhibited by a reduction of pH; pH changes modify the aggregation state of unitary channels; a negative cooperativity between extracellular/lumenal Ca(2+) and H(+) is suggested (PubMed:29019981). 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:29019981). {ECO:0000250|UniProtKB:Q9GZU1, ECO:0000269|PubMed:29019981}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | FUNCTION: Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis (PubMed:29019981). 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. 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 (PubMed:23993788, PubMed:27623384). Involved in lactosylceramide trafficking indicative for a role in the regulation of late endocytic membrane fusion/fission events. 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:25733853). Seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS-induced TFEB activation and autophagy (By similarity). Functions as a Fe(2+) permeable channel in late endosomes and lysosomes. Proposed to play a role in zinc homeostasis probably implicating its association with TMEM163 (By similarity). In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells (PubMed:17050035). {ECO:0000250|UniProtKB:Q9GZU1, ECO:0000269|PubMed:17050035, ECO:0000269|PubMed:23993788, ECO:0000269|PubMed:25733853, ECO:0000269|PubMed:27623384, ECO:0000269|PubMed:29019981}.; 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:0000250|UniProtKB:Q9GZU1}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Alternative sequence (1); Chain (1); Compositional bias (1); Disulfide bond (2); Glycosylation (2); Intramembrane (1); Modified residue (3); Motif (3); Mutagenesis (1); Region (4); Topological domain (8); Transmembrane (6) |
| Keywords | 3D-structure;Adaptive immunity;Alternative splicing;Calcium;Calcium transport;Cell membrane;Cell projection;Cytoplasmic vesicle;Disulfide bond;Endosome;Glycoprotein;Immunity;Ion channel;Ion transport;Lipid-binding;Lysosome;Membrane;Phosphoprotein;Reference proteome;Transmembrane;Transmembrane helix;Transport |
| Interact With | |
| Induction | INDUCTION: Up-regulated by nutrient starvation. {ECO:0000269|PubMed:25733853}. |
| Subcellular Location | SUBCELLULAR LOCATION: Late endosome membrane {ECO:0000250|UniProtKB:Q9GZU1}; Multi-pass membrane protein {ECO:0000269|PubMed:29019981}. Lysosome membrane {ECO:0000250|UniProtKB:Q9GZU1}; Multi-pass membrane protein {ECO:0000269|PubMed:29019981}. Cytoplasmic vesicle membrane {ECO:0000250|UniProtKB:Q9GZU1}; Multi-pass membrane protein {ECO:0000269|PubMed:29019981}. Cell projection, phagocytic cup {ECO:0000269|PubMed:23993788}. Cytoplasmic vesicle, phagosome membrane {ECO:0000269|PubMed:23993788}; Multi-pass membrane protein {ECO:0000269|PubMed:29019981}. Cell membrane {ECO:0000250|UniProtKB:Q9GZU1}; Multi-pass membrane protein {ECO:0000269|PubMed:29019981}. Note=Delivery from the trans-Golgi to lysosomes seems to occur mainly in a direct intracellular manner without intermediate delivery to the plasma membrane (By similarity). Under normal conditions, restricted to intracellular compartments so that only a very minor proportion is present at the cell membrane (PubMed:29019981). {ECO:0000250|UniProtKB:Q9GZU1, ECO:0000269|PubMed:29019981}. |
| Modified Residue | MOD_RES 10; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:17208939, ECO:0007744|PubMed:19144319"; MOD_RES 557; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:21183079"; MOD_RES 559; /note="Phosphoserine; by PAK"; /evidence="ECO:0000250|UniProtKB:Q9GZU1" |
| Post Translational Modification | PTM: Palmitoylated; involved in association with membranes. {ECO:0000250|UniProtKB:Q9GZU1}.; PTM: Phosphorylation by PKA inhibits channel activity. Dephosphorylation increases activity. {ECO:0000250|UniProtKB:Q9GZU1}.; PTM: Proteolytically cleaved probably involving multiple lysosomal proteases including cathepsin B; inhibits lysosomal channel activity. {ECO:0000250|UniProtKB:Q9GZU1}. |
| Signal Peptide | |
| Structure 3D | Electron microscopy (7) |
| Cross Reference PDB | 5WPQ; 5WPT; 5WPV; 5YDZ; 5YE1; 5YE2; 5YE5; |
| Mapped Pubmed ID | 11217851; 12466851; 16460286; 16606612; 17924347; 17989217; 18154673; 18794901; 19151629; 19322198; 19638346; 19763610; 19834762; 20095091; 20600908; 20864526; 21111738; 21267068; 22733759; 23063126; 23283937; 23382219; 23418601; 25130899; 25144769; 25216637; 25239130; 25491304; 25521295; 26010303; 26398942; 26608452; 26682800; 26950892; 27270598; 28610891; 29030399; 29131026; 29453205; 29617956; 29771310; 30479274; 30711251; 30914059; 31317194; 31806695; 31974459; 31999726; 32290105; 32576680; 32586947; 33221496; 34030116; |
| Motif | MOTIF 11..16; /note=Dileucine motif; mediates targeting to lysosomes; /evidence=ECO:0000250|UniProtKB:Q9GZU1; MOTIF 469..474; /note=Selectivity filter; /evidence=ECO:0000269|PubMed:29019981; MOTIF 573..578; /note=Dileucine internalization motif; mediates AP2 complex-dependent internalization; /evidence=ECO:0000250|UniProtKB:Q9GZU1 |
| Gene Encoded By | |
| Mass | 65,506 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |