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FLASH GENE
Symbol MCOLN1 contributors: mct/pgu - updated : 23-12-2013
HGNC name mucolipin 1
HGNC id 13356
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
  • 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
  • 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