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Protein

Mucolipin-1

Gene

Mcoln1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 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. 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 (PubMed:23993788). Involved in lactosylceramide trafficking indicative for a role in the regulation of late endocytic membrane fusion/fission events. 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:25733853). Seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS-induced TFEB activation and autophagy (By similarity). Functions as a Fe2+ 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).By similarity4 Publications
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.By similarity

Activity regulationi

Channel activity is controlled by multiple regulatory mechanisms in different subcellular compartments (By similarity). Channel function is transiently modulated by changes in Ca2+, and inhibited by a reduction of pH; pH changes modify the aggregation state of unitary channels; a negative cooperativity between extracellular/lumenal Ca2+ 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).By similarity1 Publication

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionIon channel
Biological processAdaptive immunity, Calcium transport, Immunity, Ion transport, Transport
LigandCalcium, Lipid-binding

Enzyme and pathway databases

ReactomeiR-MMU-3295583 TRP channels
R-MMU-917977 Transferrin endocytosis and recycling

Names & Taxonomyi

Protein namesi
Recommended name:
Mucolipin-1
Alternative name(s):
Mucolipidin
Transient receptor potential-mucolipin 1
Short name:
TRPML1
Gene namesi
Name:Mcoln1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 8

Organism-specific databases

MGIiMGI:1890498 Mcoln1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 65Cytoplasmic1 PublicationAdd BLAST65
Transmembranei66 – 86Helical; Name=11 PublicationAdd BLAST21
Topological domaini87 – 298Extracellular1 PublicationAdd BLAST212
Transmembranei299 – 321Helical; Name=21 PublicationAdd BLAST23
Topological domaini322 – 350Cytoplasmic1 PublicationAdd BLAST29
Transmembranei351 – 371Helical; Name=31 PublicationAdd BLAST21
Topological domaini372 – 382Extracellular1 PublicationAdd BLAST11
Transmembranei383 – 405Helical; Name=41 PublicationAdd BLAST23
Topological domaini406 – 427Cytoplasmic1 PublicationAdd BLAST22
Transmembranei428 – 448Helical; Name=51 PublicationAdd BLAST21
Topological domaini449 – 456Extracellular1 Publication8
Intramembranei457 – 477Pore-forming1 PublicationAdd BLAST21
Topological domaini478 – 491Extracellular1 PublicationAdd BLAST14
Transmembranei492 – 513Helical; Name=61 PublicationAdd BLAST22
Topological domaini514 – 580Cytoplasmic1 PublicationAdd BLAST67

Keywords - Cellular componenti

Cell membrane, Cell projection, Cytoplasmic vesicle, Endosome, Lysosome, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi432V → P: Constitutively active channel that is targeted to the cell membrane. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002153641 – 580Mucolipin-1Add BLAST580

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei10PhosphoserineCombined sources1
Disulfide bondi166 ↔ 192By similarity
Glycosylationi220N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi230N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi253 ↔ 284By similarity
Modified residuei557PhosphoserineCombined sources1
Modified residuei559Phosphoserine; by PAKBy similarity1

Post-translational modificationi

Palmitoylated; involved in association with membranes.By similarity
Phosphorylation by PKA inhibits channel activity. Dephosphorylation increases activity.By similarity
Proteolytically cleaved probably involving multiple lysosomal proteases including cathepsin B; inhibits lysosomal channnel activity.By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ99J21
PeptideAtlasiQ99J21
PRIDEiQ99J21

PTM databases

iPTMnetiQ99J21
PhosphoSitePlusiQ99J21
SwissPalmiQ99J21

Expressioni

Tissue specificityi

Widely expressed, with the highest expression in brain, liver and kidney.1 Publication

Inductioni

Up-regulated by nutrient starvation.1 Publication

Gene expression databases

BgeeiENSMUSG00000004567 Expressed in 269 organ(s), highest expression level in cardiac ventricle
CleanExiMM_MCOLN1
ExpressionAtlasiQ99J21 baseline and differential
GenevisibleiQ99J21 MM

Interactioni

Subunit structurei

Homotetramer (PubMed:29019981). Homooligomer. Can heterooligomerize with MCOLN2 or MCOLN3; heteromeric assemblies have different channel properties as compared to the respective homooligomers and may be tissue-specific. Interacts with PDCD6. Interacts with TMEM163. Interacts with LAPTM4B (By similarity).By similarity1 Publication

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000004683

Structurei

3D structure databases

ProteinModelPortaliQ99J21
SMRiQ99J21
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni42 – 62Interaction with phosphoinositides1 PublicationAdd BLAST21
Regioni107 – 121Extracellular/lumenal pore loopBy similarityAdd BLAST15
Regioni565 – 567Required for palmitoylation and association with membranesBy similarity3

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi11 – 16Dileucine motif; mediates targeting to lysosomesBy similarity6
Motifi469 – 474Selectivity filter1 Publication6
Motifi573 – 578Dileucine internalization motif; mediates AP2 complex-dependent internalizationBy similarity6

Domaini

The most N-terminal extracellular/lumenal domain (referred to as I-II linker or polycystin-mucolipin domain) contributes to a structure with a four-fold rotational symmetry in a tetrameric assembly; the structure contains a central highly electronegative pore with a 14 A diameter. The pore is critical for Ca2+ and pH regulation. The protruding structure formed by the I-II linkers may contain all the interaction sites with lipids and proteins in the endolysosomal lumen.By similarity

Sequence similaritiesi

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3733 Eukaryota
ENOG410Z1HH LUCA
GeneTreeiENSGT00390000017126
HOGENOMiHOG000232158
HOVERGENiHBG052430
InParanoidiQ99J21
KOiK04992
OMAiPANDTFN
OrthoDBiEOG091G026A
PhylomeDBiQ99J21
TreeFamiTF317783

Family and domain databases

InterProiView protein in InterPro
IPR039031 Mucolipin
IPR013122 PKD1_2_channel
PANTHERiPTHR12127 PTHR12127, 1 hit
PfamiView protein in Pfam
PF08016 PKD_channel, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 5 potential isoforms that are computationally mapped.iShow all

Isoform 1 (identifier: Q99J21-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MATPAGRRAS ETERLLTPNP GYGTQVGTSP APTTPTEEED LRRRLKYFFM
60 70 80 90 100
SPCDKFRAKG RKPCKLMLQV VKILVVTVQL ILFGLSNQLV VTFREENTIA
110 120 130 140 150
FRHLFLLGYS DGSDDTFAAY TQEQLYQAIF YAVDQYLILP EISLGRYAYV
160 170 180 190 200
RGGGGPWANG SALALCQRYY HRGHVDPAND TFDIDPRVVT DCIQVDPPDR
210 220 230 240 250
PPDIPSEDLD FLDGSASYKN LTLKFHKLIN VTIHFQLKTI NLQSLINNEI
260 270 280 290 300
PDCYTFSILI TFDNKAHSGR IPIRLETKTH IQECKHPSVS RHGDNSFRLL
310 320 330 340 350
FDVVVILTCS LSFLLCARSL LRGFLLQNEF VVFMWRRRGR EISLWERLEF
360 370 380 390 400
VNGWYILLVT SDVLTISGTV MKIGIEAKNL ASYDVCSILL GTSTLLVWVG
410 420 430 440 450
VIRYLTFFHK YNILIATLRV ALPSVMRFCC CVAVIYLGYC FCGWIVLGPY
460 470 480 490 500
HVKFRSLSMV SECLFSLING DDMFVTFAAM QAQQGHSSLV WLFSQLYLYS
510 520 530 540 550
FISLFIYMVL SLFIALITGA YDTIKHPGGT GTEKSELQAY IEQCQDSPTS
560 570 580
GKFRRGSGSA CSLFCCCGRD SPEDHSLLVN
Length:580
Mass (Da):65,506
Last modified:June 1, 2001 - v1
Checksum:iF64D2E6C5D4C041C
GO
Isoform 2 (identifier: Q99J21-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     526-580: HPGGTGTEKS...SPEDHSLLVN → RTNHRNWFSS...SSSTMWSHQV

Show »
Length:611
Mass (Da):69,853
Checksum:iC7E67D1C1DAD96AD
GO

Computationally mapped potential isoform sequencesi

There are 5 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A140LI94A0A140LI94_MOUSE
Mucolipin-1
Mcoln1
130Annotation score:
A0A140LHK5A0A140LHK5_MOUSE
Mucolipin-1
Mcoln1
94Annotation score:
A0A140LHY3A0A140LHY3_MOUSE
Mucolipin-1
Mcoln1
115Annotation score:
E0CZ07E0CZ07_MOUSE
Mucolipin-1
Mcoln1
90Annotation score:
A0A140LHW6A0A140LHW6_MOUSE
Mucolipin-1
Mcoln1
124Annotation score:

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_010821526 – 580HPGGT…SLLVN → RTNHRNWFSSFTVWIIDLNT SYQLCSKCLYLPHHLTGFLP LSYHLLLKTIYLFRGERRLC TAQCVWKLETTCGNQLSSST MWSHQV in isoform 2. 1 PublicationAdd BLAST55

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF302009 mRNA Translation: AAL58667.1
AK028385 mRNA Translation: BAC25922.1
AK034471 mRNA Translation: BAC28719.1
AK049606 mRNA Translation: BAC33838.1
BC005651 mRNA Translation: AAH05651.1
CCDSiCCDS22063.1 [Q99J21-1]
RefSeqiNP_444407.1, NM_053177.1 [Q99J21-1]
UniGeneiMm.8356

Genome annotation databases

EnsembliENSMUST00000004683; ENSMUSP00000004683; ENSMUSG00000004567 [Q99J21-1]
GeneIDi94178
KEGGimmu:94178
UCSCiuc009krq.1 mouse [Q99J21-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiMCLN1_MOUSE
AccessioniPrimary (citable) accession number: Q99J21
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: June 1, 2001
Last modified: September 12, 2018
This is version 137 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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