MCLN1_MACFA
ID MCLN1_MACFA Reviewed; 580 AA.
AC Q60HE8;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 23-NOV-2004, sequence version 1.
DT 03-AUG-2022, entry version 80.
DE RecName: Full=Mucolipin-1;
DE AltName: Full=Mucolipidin;
DE AltName: Full=Transient receptor potential channel mucolipin 1;
DE Short=TRPML1;
GN Name=MCOLN1; ORFNames=QorA-13738;
OS Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9541;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Occipital cortex;
RA Kusuda J., Osada N., Tanuma R., Hirata M., Sugano S., Hashimoto K.;
RT "Isolation and characterization of cDNA for macaque neurological disease
RT genes.";
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Nonselective cation channel probably playing a role in the
CC regulation of membrane trafficking events and of metal homeostasis.
CC Proposed to play a major role in Ca(2+) release from late endosome and
CC lysosome vesicles to the cytoplasm, which is important for many
CC lysosome-dependent cellular events, including the fusion and
CC trafficking of these organelles, exocytosis and autophagy. Required for
CC efficient uptake of large particles in macrophages in which Ca(2+)
CC release from the lysosomes triggers lysosomal exocytosis. May also play
CC a role in phagosome-lysosome fusion. Involved in lactosylceramide
CC trafficking indicative for a role in the regulation of late endocytic
CC membrane fusion/fission events. By mediating lysosomal Ca(2+) release
CC is involved in regulation of mTORC1 signaling and in mTOR/TFEB-
CC dependent lysosomal adaptation to environmental cues such as nutrient
CC levels. Seems to act as lysosomal active oxygen species (ROS) sensor
CC involved in ROS-induced TFEB activation and autophagy. Functions as a
CC Fe(2+) permeable channel in late endosomes and lysosomes. Proposed to
CC play a role in zinc homeostasis probably implicating its association
CC with TMEM163. In adaptive immunity, TRPML2 and TRPML1 may play
CC redundant roles in the function of the specialized lysosomes of B
CC cells. {ECO:0000250|UniProtKB:Q99J21, ECO:0000250|UniProtKB:Q9GZU1}.
CC -!- FUNCTION: May contribute to cellular lipase activity within the late
CC endosomal pathway or at the cell surface which may be involved in
CC processes of membrane reshaping and vesiculation, especially the growth
CC of tubular structures. However, it is not known, whether it conveys the
CC enzymatic activity directly, or merely facilitates the activity of an
CC associated phospholipase. {ECO:0000250|UniProtKB:Q9GZU1}.
CC -!- ACTIVITY REGULATION: Channel activity is controlled by multiple
CC regulatory mechanisms in different subcellular compartments. Channel
CC function is transiently modulated by changes in Ca(2+), and inhibited
CC by a reduction of pH; pH changes modify the aggregation state of
CC unitary channels; a negative cooperativity between
CC extracellular/lumenal Ca(2+) and H(+) is suggested. Regulated by
CC phosphoinositides in a compartment-specific manner: in lysosomes
CC activated by PtdIns(3,5)P2 (Phosphatidylinositol 3,5-bisphosphate) and
CC at the plasma membrane inhibited by PtdIns(4,5)P2 (Phosphatidylinositol
CC 4,5-bisphosphate). {ECO:0000250|UniProtKB:Q9GZU1}.
CC -!- SUBUNIT: Homotetramer. Homooligomer. Can heterooligomerize with MCOLN2
CC or MCOLN3; heteromeric assemblies have different channel properties as
CC compared to the respective homooligomers and may be tissue-specific.
CC Interacts with PDCD6. Interacts with TMEM163. Interacts with LAPTM4B.
CC {ECO:0000250|UniProtKB:Q9GZU1}.
CC -!- SUBCELLULAR LOCATION: Late endosome membrane
CC {ECO:0000250|UniProtKB:Q9GZU1}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9GZU1}. Lysosome membrane
CC {ECO:0000250|UniProtKB:Q9GZU1}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9GZU1}. Cytoplasmic vesicle membrane
CC {ECO:0000250|UniProtKB:Q9GZU1}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9GZU1}. Cell projection, phagocytic cup
CC {ECO:0000250|UniProtKB:Q99J21}. Cytoplasmic vesicle, phagosome membrane
CC {ECO:0000250|UniProtKB:Q99J21}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9GZU1}. Cell membrane
CC {ECO:0000250|UniProtKB:Q9GZU1}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9GZU1}. Note=Delivery from the trans-Golgi to
CC lysosomes seems to occur mainly in a direct intracellular manner
CC without intermediate delivery to the plasma membrane. Under normal
CC conditions, restricted to intracellular compartments so that only a
CC very minor proportion is present at the cell membrane.
CC {ECO:0000250|UniProtKB:Q9GZU1}.
CC -!- DOMAIN: The most N-terminal extracellular/lumenal domain (referred to
CC as I-II linker or polycystin-mucolipin domain) contributes to a
CC structure with a four-fold rotational symmetry in a tetrameric
CC assembly; the structure contains a central highly electronegative pore
CC with a 14 A diameter. The pore is critical for Ca(2+) and pH
CC regulation. The protruding structure formed by the I-II linkers may
CC contain all the interaction sites with lipids and proteins in the
CC endolysosomal lumen. {ECO:0000250|UniProtKB:Q9GZU1}.
CC -!- PTM: Palmitoylated; involved in association with membranes.
CC {ECO:0000250|UniProtKB:Q9GZU1}.
CC -!- PTM: Phosphorylation by PKA inhibits channel activity.
CC Dephosphorylation increases activity. {ECO:0000250|UniProtKB:Q9GZU1}.
CC -!- PTM: Proteolytically cleaved probably involving multiple lysosomal
CC proteases including cathepsin B; inhibits lysosomal channel activity.
CC {ECO:0000250|UniProtKB:Q9GZU1}.
CC -!- SIMILARITY: Belongs to the transient receptor (TC 1.A.4) family.
CC Polycystin subfamily. MCOLN1 sub-subfamily. {ECO:0000305}.
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DR EMBL; AB125179; BAD51967.1; -; mRNA.
DR RefSeq; NP_001270027.1; NM_001283098.1.
DR AlphaFoldDB; Q60HE8; -.
DR SMR; Q60HE8; -.
DR STRING; 9541.XP_005587812.1; -.
DR GeneID; 102143748; -.
DR CTD; 57192; -.
DR eggNOG; KOG3733; Eukaryota.
DR OrthoDB; 1379516at2759; -.
DR Proteomes; UP000233100; Unplaced.
DR GO; GO:0042995; C:cell projection; IEA:UniProtKB-KW.
DR GO; GO:0016021; C:integral component of membrane; ISS:UniProtKB.
DR GO; GO:0005770; C:late endosome; ISS:UniProtKB.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005765; C:lysosomal membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR GO; GO:0001891; C:phagocytic cup; IEA:UniProtKB-SubCell.
DR GO; GO:0030670; C:phagocytic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0097682; F:intracellular phosphatidylinositol-3,5-bisphosphate-sensitive cation channel activity; ISS:UniProtKB.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0006816; P:calcium ion transport; IEA:UniProtKB-KW.
DR GO; GO:0098655; P:cation transmembrane transport; ISS:UniProtKB.
DR GO; GO:0071277; P:cellular response to calcium ion; ISS:UniProtKB.
DR GO; GO:0071467; P:cellular response to pH; ISS:UniProtKB.
DR GO; GO:0051289; P:protein homotetramerization; ISS:UniProtKB.
DR InterPro; IPR039031; Mucolipin.
DR InterPro; IPR013122; PKD1_2_channel.
DR PANTHER; PTHR12127; PTHR12127; 1.
DR Pfam; PF08016; PKD_channel; 1.
PE 2: Evidence at transcript level;
KW Adaptive immunity; Calcium; Calcium transport; Cell membrane;
KW Cell projection; Cytoplasmic vesicle; Disulfide bond; Endosome;
KW Glycoprotein; Immunity; Ion channel; Ion transport; Lipid-binding;
KW Lysosome; Membrane; Phosphoprotein; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..580
FT /note="Mucolipin-1"
FT /id="PRO_0000215363"
FT TOPO_DOM 1..65
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TRANSMEM 66..86
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TOPO_DOM 87..298
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TRANSMEM 299..321
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TOPO_DOM 322..350
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TRANSMEM 351..371
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TOPO_DOM 372..382
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TRANSMEM 383..405
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TOPO_DOM 406..427
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TRANSMEM 428..448
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TOPO_DOM 449..456
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT INTRAMEM 457..477
FT /note="Pore-forming"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TOPO_DOM 478..491
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TRANSMEM 492..513
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT TOPO_DOM 514..580
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT REGION 1..38
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 42..62
FT /note="Interaction with phosphoinositides"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT REGION 107..121
FT /note="Extracellular/lumenal pore loop"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT REGION 565..567
FT /note="Required for palmitoylation and association with
FT membranes"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT MOTIF 11..16
FT /note="Dileucine motif; mediates targeting to lysosomes"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT MOTIF 469..474
FT /note="Selectivity filter"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT MOTIF 573..578
FT /note="Dileucine internalization motif; mediates AP2
FT complex-dependent internalization"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT MOD_RES 10
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q99J21"
FT MOD_RES 557
FT /note="Phosphoserine; by PAK"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT MOD_RES 559
FT /note="Phosphoserine; by PAK"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT CARBOHYD 230
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 166..192
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT DISULFID 253..284
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
SQ SEQUENCE 580 AA; 65203 MW; 6B59A74F0231FD75 CRC64;
MTDPAGPRGS ETERLLTPNP GYGTQVGPSP APPTPPEEED LRRRLKYFFM SPCDKFRAKG
RKPCKLMLQV VKILVVTVQL ILFGLSNQLA VTFREENTIA FRHLFLLGYS DGADDTFAAY
TQEQLYQAIF HAVDQYLALP DVSLGRYAYV HGGGDPWTNG SGLALCQRYY HRGHVDPAND
TFDIDPMVVT DCIQVDPPER PPPSPSDDLA LLEGSSSYKN LTLKFHKLVN VTIHFRLKTI
NLQSLINNEI PDCYTFSVLI TFDNKAHSGR IPISLETQAH IQECKHPSVF RHGDNSFRLL
FDVVVILTCS LSFLLCARSL LRGFLLQNEF VRFMWRQRRR VISLWERLEF VNGWYILLVT
SDVLTISGTI MKIGIEAKNL ASYDVCSILL GTSTLLVWVG VIRYLTFFHN YNILIATLRV
ALPSVMRFCC CVAVIYLGYC FCGWIVLGPY HVKFRSLSMV SECLFSLING DDMFVTFAAM
QAQQGRSSLV WLFSQLYLYS FISLFIYMVL SLFIALITGA YDTIKHPGGA GAEESELQAY
IAQCQDSPTS GKFRRGSGSA CSLLCCCGRD PSEEHSLLVN
