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Protein

Mucolipin-3

Gene

MCOLN3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Nonselective cation channel probably playing a role in the regulation of membrane trafficking events. Acts as Ca2+-permeable cation channel with inwardly rectifying activity (PubMed:18369318, PubMed:19497048, PubMed:19522758, PubMed:19885840). Mediates release of Ca2+ from endosomes to the cytoplasm, contributes to endosomal acidification and is involved in the regulation of membrane trafficking and fusion in the endosomal pathway (PubMed:21245134). Does not seem to act as mechanosensory transduction channel in inner ear sensory hair cells. Proposed to play a critical role at the cochlear stereocilia ankle-link region during hair-bundle growth (By similarity). Involved in the regulation of autophagy (PubMed:19522758). Through association with GABARAPL2 may be involved in autophagosome formation possibly providing Ca2+ for the fusion process (By similarity). Through a possible and probably tissue-specific heteromerization with MCOLN1 may be at least in part involved in many lysosome-dependent cellular events (PubMed:19885840). Possible heteromeric ion channel assemblies with TRPV5 show pharmacological similarity with TRPML3 (PubMed:23469151).By similarityCurated6 Publications

Enzyme regulationi

Inhibited by lumenal H+ and Na+ (PubMed:18369318). The channel pore shows dynamic behavior and undergoes spontaneous, Ca2+-dependent modulation when conducting Ca2+ (PubMed:20378547).2 Publications

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionIon channel
Biological processIon transport, Transport

Enzyme and pathway databases

ReactomeiR-HSA-3295583. TRP channels.

Protein family/group databases

TCDBi1.A.5.3.4. the polycystin cation channel (pcc) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Mucolipin-3
Alternative name(s):
Transient receptor potential channel mucolipin 3
Short name:
TRPML3
Gene namesi
Name:MCOLN3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000055732.12.
HGNCiHGNC:13358. MCOLN3.

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 – 62CytoplasmicCuratedAdd BLAST62
Transmembranei63 – 83HelicalSequence analysisAdd BLAST21
Topological domaini84 – 283ExtracellularCuratedAdd BLAST200
Transmembranei284 – 304HelicalSequence analysisAdd BLAST21
Topological domaini305 – 336CytoplasmicCuratedAdd BLAST32
Transmembranei337 – 357HelicalSequence analysisAdd BLAST21
Topological domaini358 – 374ExtracellularCuratedAdd BLAST17
Transmembranei375 – 395HelicalSequence analysisAdd BLAST21
Topological domaini396 – 414CytoplasmicCuratedAdd BLAST19
Transmembranei415 – 435HelicalSequence analysisAdd BLAST21
Topological domaini436 – 479ExtracellularCuratedAdd BLAST44
Transmembranei480 – 500HelicalSequence analysisAdd BLAST21
Topological domaini501 – 553CytoplasmicCuratedAdd BLAST53

Keywords - Cellular componenti

Cell membrane, Cytoplasmic vesicle, Endosome, Lysosome, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi252H → A: Increases inhibition by lumenal H(+). Decreases inhibition by lumenal H(+); when associated with A-283. 1 Publication1
Mutagenesisi273H → A: Increases inhibition by lumenal H(+). Decreases inhibition by lumenal H(+); when associated with A-283. 1 Publication1
Mutagenesisi283H → A: Constitutive active channel; abolishes inhibition by lumenal H(+); retains the Ca(2+)-dependent inactivation of the Ca(2+) current. Decreases inhibition by lumenal H(+); when associated with A-252. Decreases inhibition by lumenal H(+); when associated with A-273. 1 Publication1
Mutagenesisi283H → R: Increases inhibition by lumenal H(+). 1 Publication1
Mutagenesisi419A → P: Constitutive active channel; abolishes inhibition by lumenal H(+); increases the pore diameter. 2 Publications1
Mutagenesisi449E → A: Constitutive active channel; greatly impairs inhibition by lumenal Na(+). 1 Publication1
Mutagenesisi449E → K: Abolishes channel activity. 1 Publication1
Mutagenesisi458 – 459DD → KK: Enhances endocytosis. 1 Publication2
Mutagenesisi458D → K: Nearly abolishes channel activity; inhibits starvation-induced autophagy. 1 Publication1
Mutagenesisi459D → A: Decreases in Ca(2+) permeability and selectivity; decreases channel pore dynamic behavior. 1 Publication1

Organism-specific databases

DisGeNETi55283.
OpenTargetsiENSG00000055732.
PharmGKBiPA134947324.

Chemistry databases

ChEMBLiCHEMBL1293243.
GuidetoPHARMACOLOGYi503.

Polymorphism and mutation databases

BioMutaiMCOLN3.
DMDMi50401084.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002153671 – 553Mucolipin-3Add BLAST553

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi159 ↔ 185By similarity
Disulfide bondi238 ↔ 269By similarity

Post-translational modificationi

N-glycosylated.1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

MaxQBiQ8TDD5.
PaxDbiQ8TDD5.
PeptideAtlasiQ8TDD5.
PRIDEiQ8TDD5.

PTM databases

iPTMnetiQ8TDD5.
PhosphoSitePlusiQ8TDD5.
SwissPalmiQ8TDD5.

Expressioni

Gene expression databases

BgeeiENSG00000055732.
CleanExiHS_MCOLN3.
ExpressionAtlasiQ8TDD5. baseline and differential.
GenevisibleiQ8TDD5. HS.

Organism-specific databases

HPAiHPA018106.
HPA062137.

Interactioni

Subunit structurei

Forms homooligomeric complexes; probably tetrameric (By similarity). Can heterooligomerize with MCOLN1; heteromeric assemblies have different channel properties as compared to the respective homooligomers and may be tissue-specific (PubMed:19885840). May heterooligomerize with TRPV5 to form a functional distinct ion channel (PubMed:23469151). Interacts with GABARAPL2 (By similarity).By similarity1 Publication1 Publication

Protein-protein interaction databases

BioGridi120571. 60 interactors.
IntActiQ8TDD5. 1 interactor.
STRINGi9606.ENSP00000304843.

Chemistry databases

BindingDBiQ8TDD5.

Structurei

3D structure databases

ProteinModelPortaliQ8TDD5.
SMRiQ8TDD5.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni104 – 118Extracellular/lumenal pore loopBy similarityAdd BLAST15

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.
InParanoidiQ8TDD5.
KOiK04994.
OMAiCGWLILG.
OrthoDBiEOG091G026A.
PhylomeDBiQ8TDD5.
TreeFamiTF317783.

Family and domain databases

InterProiView protein in InterPro
IPR013122. PKD1_2_channel.
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

Isoform 1 (identifier: Q8TDD5-1) [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
MADPEVVVSS CSSHEEENRC NFNQQTSPSE ELLLEDQMRR KLKFFFMNPC
60 70 80 90 100
EKFWARGRKP WKLAIQILKI AMVTIQLVLF GLSNQMVVAF KEENTIAFKH
110 120 130 140 150
LFLKGYMDRM DDTYAVYTQS DVYDQLIFAV NQYLQLYNVS VGNHAYENKG
160 170 180 190 200
TKQSAMAICQ HFYKRGNIYP GNDTFDIDPE IETECFFVEP DEPFHIGTPA
210 220 230 240 250
ENKLNLTLDF HRLLTVELQF KLKAINLQTV RHQELPDCYD FTLTITFDNK
260 270 280 290 300
AHSGRIKISL DNDISIRECK DWHVSGSIQK NTHYMMIFDA FVILTCLVSL
310 320 330 340 350
ILCIRSVIRG LQLQQEFVNF FLLHYKKEVS VSDQMEFVNG WYIMIIISDI
360 370 380 390 400
LTIIGSILKM EIQAKSLTSY DVCSILLGTS TMLVWLGVIR YLGFFAKYNL
410 420 430 440 450
LILTLQAALP NVIRFCCCAA MIYLGYCFCG WIVLGPYHDK FRSLNMVSEC
460 470 480 490 500
LFSLINGDDM FATFAKMQQK SYLVWLFSRI YLYSFISLFI YMILSLFIAL
510 520 530 540 550
ITDTYETIKQ YQQDGFPETE LRTFISECKD LPNSGKYRLE DDPPVSLFCC

CKK
Length:553
Mass (Da):64,248
Last modified:June 1, 2002 - v1
Checksum:i2E63DA196379F9E3
GO
Isoform 2 (identifier: Q8TDD5-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     77-132: Missing.

Show »
Length:497
Mass (Da):57,723
Checksum:iB014DF953C034761
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti9S → C in BAA91951 (PubMed:14702039).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_01082377 – 132Missing in isoform 2. 1 PublicationAdd BLAST56

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF475085 mRNA. Translation: AAL84622.1.
AK001868 mRNA. Translation: BAA91951.1.
AL358789 Genomic DNA. No translation available.
CCDSiCCDS58009.1. [Q8TDD5-2]
CCDS701.1. [Q8TDD5-1]
RefSeqiNP_001240622.1. NM_001253693.1. [Q8TDD5-2]
NP_060768.8. NM_018298.10. [Q8TDD5-1]
XP_005271060.1. XM_005271003.1. [Q8TDD5-1]
XP_006710813.1. XM_006710750.1. [Q8TDD5-1]
UniGeneiHs.535239.

Genome annotation databases

EnsembliENST00000341115; ENSP00000342698; ENSG00000055732. [Q8TDD5-2]
ENST00000370589; ENSP00000359621; ENSG00000055732. [Q8TDD5-1]
GeneIDi55283.
KEGGihsa:55283.
UCSCiuc001dkp.4. human. [Q8TDD5-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiMCLN3_HUMAN
AccessioniPrimary (citable) accession number: Q8TDD5
Secondary accession number(s): Q5T4H5, Q5T4H6, Q9NV09
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: June 1, 2002
Last modified: November 22, 2017
This is version 125 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families