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FLASH GENE
Symbol MCOLN1 contributors: mct/pgu - updated : 23-12-2017
HGNC name mucolipin 1
HGNC id 13356
Corresponding disease
ML4 mucolipidosis IV
Location 19p13.2      Physical location : 7.587.495 - 7.598.894
Synonym name
  • mucolipidine
  • novel transient receptor potential channel
  • type IV mucolipidosis-associated protein
    • Synonym symbol(s) MST080, MSTP080, TRP-ML1, TRPML1, MG-2
    DNA
    TYPE functioning gene
    STRUCTURE 11.35 kb     14 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    motif repetitive sequence   ALU   long interspersed repetitive elements   other
    MAPPING cloned Y linked N status confirmed
    Map pter - INSR - D19S592 - D19S406 - D19S1191 - D19S901 - D19S1184 - D19S873 - ARHGEF18 - MCOLN1 - PNPLA6 - D19S1189 - D19S1186 - NEZHA - STXBP2 - D19S76 - cen
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    14 - 2051 65 580 - 2011 11318610
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinesmall intestine  highly
    Lymphoid/Immunelymph node   highly
    Nervousbrain   highly
    Reproductivemale systemtestis  highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • AAs 37-49 are a new PDCD6-binding domain
  • one transmembrane helix
  • six predicted transmembrane domains
  • intracellular N- and C-terminus regions
  • two proline rich region
  • a consensus motif of lipases in first half of the protein
  • a bipartite nuclear localization signal(NLS)
  • six transmembrane-spanning domains with both amino- and carboxyl-terminal tails having a cytosolic orientation and the pore located between transmembrane segments 5 and 6, in C terminal half containing Ser(557), principal phosphorylation site and Ser(559)
  • two PKA (protein kinase A) consensus motifs
  • a 53-AA C-terminal region required for efficient exit from the Golgi
    • HOMOLOGY
    intraspecies homolog to PKD2
    Homologene
    FAMILY
  • transient receptor (TRP) superfamily
  • polycystin subfamily
  • mucolipin subfamily of transient receptor potential (TRP) proteins
    • CATEGORY enzyme , transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    text
  • translocated to the plasma membrane during lysosomal exocytosis
  • late endosomal and lysosomal ion channel protein
  • efficient lysosomal targeting requires di-leucine motifs in both the N-terminal and the C-terminal cytosolic tails
  • localized to later compartments along the endocytic pathway (late endosomes and lysosomes
    • basic FUNCTION
  • late endosomal and lysosomal ion channel protein, involved in Ca2+ transport regulating lysosomal exocytosis and trafficking of late endosomes and lysosomes
  • involved in the acidification and in endosomal function
  • playing a major role in Ca(2+) transport regulating lysosomal exocytosis and potentially other phenomena related to the trafficking of late endosomes and lysosomes
  • functions as a Fe2+ permeable channel in late endosomes and lysosomes
  • correct localization of mucolipin-1 and the integrity of its ion pore are essential for its physiological function in the late endocytic pathway
  • with MCOLN2, dictate the localization of MCOLN3 and not vice versa
  • lysosomal membrane protein believed to play a role in endosomal-lysosomal interaction, lysosomal pH stability, lysosome maturation, lipid metabolism, and autophagy
  • activation of MCOLN1 in late endosome and lysosome may lead to the appearance of MCOLN1 proteins at the plasma membrane
  • has been suggested to regulate fusion/fission of vesicles in the endocytic pathway and/or some aspect of lysosomal ion homeostasis such as pH, iron, or zinc content
  • ion channel that regulates membrane transport along the endolysosomal pathway
  • releasing luminal Ca2+ mediated by MCOLN1 and promoting interaction with PDCD6 along with the PDCD6-dependent recruitment of other proteins implicated in fusion/fission events
  • involved in membrane remodeling and the formation of extensions suggests that it may play a role in the formation of cellular processes linked to the late endosome/lysosome (LE/L) pathway
  • mechanistic link between acute TRPML1 loss and cell death
  • potential role in zinc transport
  • lysosomal ion channel permeable to cations, including Fe2+
  • redistributes potentially Fe2+ between the lysosomes and the cytoplasm
  • its role in the cell extends outside lysosomes
  • TMEM163 and MCOLN1 proteins play a critical role in cellular zinc homeostasis
  • lysosomal ion channel MCOLN1 and the poorly understood novel transporter TMEM163 have been shown to play a role in the Zn2+ uptake by the lysosomes
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS exocytosis transport , electron transport
    text cellular trafficking, autophagy, lysosomal biogenesis, lysosomal iron release and lysospmal exocytosis
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • selectivity for ions Na+, K+, Ca2+, Mn2+, Fe2+, Mg2+, Zn2+
    • protein
  • interacting with MCOLN2, MCOLN3, HSC70, HSP40, ALG-2
  • MCOLN1 and TPCN1 are present in the same complex, they function as two independent organellar ion channels and TPCN1, but not MCOLN1 are the targets for NAADP
  • its loss specifically causes, an increase in the lysosomal protease CTSB and the lysosomal membrane protein LAMP1
  • co-expression of MCOLN1 with kinase-inactive protein kinase D (PRKD1 or PRKD2) inhibited MCOLN1 Golgi exit and transport to lysosomes and decreased MCOLN1 cleavage
  • MCOLN1 channel-mediated lysosomal Ca(2+) bursts upon FASLG stimulation promote lysosome trafficking and interactions with the sarcoplasmic reticulum, leading to apoptosis of coronary arterial myocytes via a Ca(2+)-dependent mechanism
  • works potentially in concert with SLC30A4 to regulate zinc translocation between the cytoplasm and lysosomes
  • TMEM163 protein, a putative zinc transporter, is a novel interacting partner for MCOLN1
  • MCOLN1 positively regulates TLR7 responses in dendritic cells by facilitating RNA transportation to lysosomes
  • lysosomal Ca2+ release through MCOLN1 activates PPP3CA, which binds and dephosphorylates &
    • 8203;TFEB, thus promoting its nuclear translocation
    cell & other
    REGULATION
    activated by extracellular or luminal low pH
    inhibited by Gd3+, La3+, verapamil
    Other regulated by phosphorylation
    regulated by PDCD6 (modulates the function of MCOLN1 along the late endosomal-lysosomal pathway)
    ASSOCIATED DISORDERS
    corresponding disease(s) ML4
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    results in intracellular chelatable zinc dyshomeostasis
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • TRPML1 K.O mice show inclusion bodies, enlarged vacuoles, psychomotor defect, retinal degeneration, death at age approximately 8 months
  • neonatal enterocytes of mice lacking both mucolipins (Trpml3-/-;Trpml1-/-) vacuolated pathologically within hours of birth and remained so until weaning