MCOLN1

This gene encodes a memberof the transient receptor potential (TRP) cation channel gene family. The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, and functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca(2+), Fe(2+), Na(+), K(+), and H(+), and is modulated by changes in Ca(2+) concentration. Mutations in this gene result in mucolipidosis type IV.

MUCOLIPIN 1

Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis. Proposed to play a major role in Ca2+ 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:15336987, PubMed:14749347, PubMed:29019983, PubMed:27623384).

Required for efficient uptake of large particles in macrophages in which Ca2+ 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 Ca2+ release is involved in regulation of mTORC1 signaling and in mTOR/TFEB-dependent lysosomal adaptation to environmental cues such as nutrient levels (PubMed:27787197, PubMed:25733853).

Seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS-induced TFEB activation and autophagy (PubMed:27357649).

Functions as a Fe2+ permeable channel in late endosomes and lysosomes (PubMed:18794901).

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).

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.

Adaptive immune response Source: UniProtKB-KW
Autophagosome maturation Source: Ensembl
Calcium ion transmembrane transport Source: UniProtKB
Cation transport Source: UniProtKB
Cellular response to calcium ion Source: UniProtKB
Cellular response to pH Source: UniProtKB
Phagosome maturation Source: UniProtKB
Protein homotetramerization Source: UniProtKB
Transferrin transport Source: Reactome

Endosome
Late endosome membrane
Lysosome
Lysosome membrane
Plasma membrane
Cell membrane
Other locations
Cytoplasmic vesicle membrane
phagocytic cup
phagosome membrane
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).

Mucolipidosis 4 (ML4):
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.

Cytoplasmic: 1-65
Helical: 66-86
Extracellular: 87-298
Helical: 299-321
Cytoplasmic: 322-350
Helical: 351-371
Extracellular: 372-382
Helical: 383-405
Cytoplasmic: 406-427
Helical: 428-448
Extracellular: 449-456
Pore-forming: 457-477
Extracellular: 478-491
Helical: 492-513
Cytoplasmic: 514-580

Palmitoylated; involved in association with membranes.
Phosphorylation by PKA inhibits channel activity. Dephosphorylation increases activity.
Proteolytically cleaved probably involving multiple lysosomal proteases including cathepsin B; inhibits lysosomal channel activity (PubMed:16257972).