MCLN3_MOUSE
ID MCLN3_MOUSE Reviewed; 553 AA.
AC Q8R4F0; Q8BS73; Q8BSG1; Q8CDB2;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2002, sequence version 1.
DT 03-AUG-2022, entry version 139.
DE RecName: Full=Mucolipin-3;
DE AltName: Full=Transient receptor potential channel mucolipin 3;
DE Short=TRPML3;
GN Name=Mcoln3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND VARIANTS THR-362 AND
RP PRO-419.
RC STRAIN=C57BL/6J;
RX PubMed=12403827; DOI=10.1073/pnas.222425399;
RA Di Palma F., Belyantseva I.A., Kim H.J., Vogt T.F., Kachar B.,
RA Noben-Trauth K.;
RT "Mutations in Mcoln3 associated with deafness and pigmentation defects in
RT varitint-waddler (Va) mice.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:14994-14999(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6J;
RA Falardeau J.L., Kennedy J.C., Acierno J.S. Jr., Slaugenhaupt S.A.;
RT "Cloning of the mouse Mcoln3 gene.";
RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Embryo, Mesonephros, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP FUNCTION, MUTAGENESIS OF 458-ASP-ASP-459, AND CHARACTERIZATION OF VARIANT
RP PRO-419.
RX PubMed=17989217; DOI=10.1073/pnas.0709096104;
RA Xu H., Delling M., Li L., Dong X., Clapham D.E.;
RT "Activating mutation in a mucolipin transient receptor potential channel
RT leads to melanocyte loss in varitint-waddler mice.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:18321-18326(2007).
RN [5]
RP CHARACTERIZATION OF VARIANT PRO-419.
RX PubMed=18048323; DOI=10.1073/pnas.0709846104;
RA Grimm C., Cuajungco M.P., van Aken A.F., Schnee M., Joers S., Kros C.J.,
RA Ricci A.J., Heller S.;
RT "A helix-breaking mutation in TRPML3 leads to constitutive activity
RT underlying deafness in the varitint-waddler mouse.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:19583-19588(2007).
RN [6]
RP FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=18801844; DOI=10.1113/jphysiol.2008.156992;
RA van Aken A.F., Atiba-Davies M., Marcotti W., Goodyear R.J., Bryant J.E.,
RA Richardson G.P., Noben-Trauth K., Kros C.J.;
RT "TRPML3 mutations cause impaired mechano-electrical transduction and
RT depolarization by an inward-rectifier cation current in auditory hair cells
RT of varitint-waddler mice.";
RL J. Physiol. (Lond.) 586:5403-5418(2008).
RN [7]
RP DISRUPTION PHENOTYPE.
RX PubMed=21179200; DOI=10.1371/journal.pone.0014317;
RA Joers S., Grimm C., Becker L., Heller S.;
RT "Genetic inactivation of Trpml3 does not lead to hearing and vestibular
RT impairment in mice.";
RL PLoS ONE 5:E14317-E14317(2010).
RN [8]
RP FUNCTION, INTERACTION WITH GABARAPL2, AND SUBCELLULAR LOCATION.
RX PubMed=24269818; DOI=10.1016/j.bbrc.2013.11.044;
RA Choi S., Kim H.J.;
RT "The Ca2+ channel TRPML3 specifically interacts with the mammalian ATG8
RT homologue GATE16 to regulate autophagy.";
RL Biochem. Biophys. Res. Commun. 443:56-61(2014).
CC -!- FUNCTION: Nonselective ligand-gated cation channel probably playing a
CC role in the regulation of membrane trafficking events. Acts as Ca(2+)-
CC permeable cation channel with inwardly rectifying activity
CC (PubMed:17989217). Mediates release of Ca(2+) from endosomes to the
CC cytoplasm, contributes to endosomal acidification and is involved in
CC the regulation of membrane trafficking and fusion in the endosomal
CC pathway (By similarity). Does not seem to act as mechanosensory
CC transduction channel in inner ear sensory hair cells. Proposed to play
CC a critical role at the cochlear stereocilia ankle-link region during
CC hair-bundle growth (PubMed:18801844). Involved in the regulation of
CC autophagy. Through association with GABARAPL2 may be involved in
CC autophagosome formation possibly providing Ca(2+) for the fusion
CC process (PubMed:24269818). Through a possible and probably tissue-
CC specific heteromerization with MCOLN1 may be at least in part involved
CC in many lysosome-dependent cellular events. Possible heteromeric ion
CC channel assemblies with TRPV5 show pharmacological similarity with
CC TRPML3 (By similarity). {ECO:0000250|UniProtKB:Q8TDD5,
CC ECO:0000269|PubMed:17989217, ECO:0000269|PubMed:18801844,
CC ECO:0000269|PubMed:24269818}.
CC -!- ACTIVITY REGULATION: Inhibited by lumenal H(+) and Na(+). The channel
CC pore shows dynamic behavior and undergoes spontaneous, Ca(2+)-dependent
CC modulation when conducting Ca(2+). {ECO:0000250|UniProtKB:Q8TDD5}.
CC -!- SUBUNIT: Homotetramer. Can heterooligomerize with MCOLN1; heteromeric
CC assemblies have different channel properties as compared to the
CC respective homooligomers and may be tissue-specific. May
CC heterooligomerize with TRPV5 to form a functional distinct ion channel
CC (By similarity). Interacts with GABARAPL2 (PubMed:24269818).
CC {ECO:0000250|UniProtKB:Q8TDD5, ECO:0000269|PubMed:24269818}.
CC -!- SUBCELLULAR LOCATION: Early endosome membrane
CC {ECO:0000250|UniProtKB:Q8TDD5}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:F6RG56}. Late endosome membrane
CC {ECO:0000269|PubMed:17989217}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:F6RG56}. Cytoplasmic vesicle, autophagosome
CC membrane {ECO:0000269|PubMed:24269818}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:F6RG56}. Cell projection, stereocilium membrane
CC {ECO:0000269|PubMed:18801844}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:F6RG56}. Note=Recycles between the plasma
CC membrane and intracellular compartments by a dynamin-dependent
CC endocytic pathway (By similarity). In the cochlea located at the base
CC of stereocilia near the position of the ankle links.
CC {ECO:0000250|UniProtKB:Q8TDD5, ECO:0000269|PubMed:18801844}.
CC -!- TISSUE SPECIFICITY: Expressed in the cochlea; particularly in the inner
CC and outer hair cells (at protein level). {ECO:0000269|PubMed:12403827,
CC ECO:0000269|PubMed:18801844}.
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: N-glycosylated. {ECO:0000250|UniProtKB:Q8TDD5}.
CC -!- DISEASE: Note=Defects in Mcoln3 are the cause of the varitin-waddler
CC (Va) phenotype. Classical Va mice exhibit early-onset hearing loss,
CC vestibular defects, pigmentation abnormalities and perinatal lethality.
CC The phenotype varitin-waddler Jackcon (Va-J), which arose in a cross
CC segregating for Va, is similar but less severe.
CC {ECO:0000269|PubMed:12403827, ECO:0000269|PubMed:18048323}.
CC -!- DISRUPTION PHENOTYPE: No severe auditory and vestibular phenotype; does
CC not lead to circling behavior, balance impairment or hearing loss.
CC {ECO:0000269|PubMed:21179200}.
CC -!- SIMILARITY: Belongs to the transient receptor (TC 1.A.4) family.
CC Polycystin subfamily. MCOLN3 sub-subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC27146.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAC28123.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAC28916.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AY083531; AAM08924.1; -; mRNA.
DR EMBL; AF475086; AAL84623.1; -; mRNA.
DR EMBL; AK030819; BAC27146.1; ALT_INIT; mRNA.
DR EMBL; AK033008; BAC28123.1; ALT_INIT; mRNA.
DR EMBL; AK035029; BAC28916.1; ALT_INIT; mRNA.
DR CCDS; CCDS17900.1; -.
DR RefSeq; NP_598921.1; NM_134160.1.
DR RefSeq; XP_006501144.1; XM_006501081.2.
DR RefSeq; XP_006501145.1; XM_006501082.3.
DR RefSeq; XP_006501146.1; XM_006501083.3.
DR RefSeq; XP_006501147.1; XM_006501084.3.
DR AlphaFoldDB; Q8R4F0; -.
DR SMR; Q8R4F0; -.
DR STRING; 10090.ENSMUSP00000038801; -.
DR GuidetoPHARMACOLOGY; 503; -.
DR TCDB; 1.A.5.3.2; the polycystin cation channel (pcc) family.
DR GlyGen; Q8R4F0; 2 sites.
DR iPTMnet; Q8R4F0; -.
DR PhosphoSitePlus; Q8R4F0; -.
DR SwissPalm; Q8R4F0; -.
DR MaxQB; Q8R4F0; -.
DR PaxDb; Q8R4F0; -.
DR PRIDE; Q8R4F0; -.
DR ProteomicsDB; 252751; -.
DR ABCD; Q8R4F0; 1 sequenced antibody.
DR Antibodypedia; 19787; 151 antibodies from 28 providers.
DR DNASU; 171166; -.
DR Ensembl; ENSMUST00000039450; ENSMUSP00000038801; ENSMUSG00000036853.
DR GeneID; 171166; -.
DR KEGG; mmu:171166; -.
DR UCSC; uc008rqx.1; mouse.
DR CTD; 55283; -.
DR MGI; MGI:1890500; Mcoln3.
DR VEuPathDB; HostDB:ENSMUSG00000036853; -.
DR eggNOG; KOG3733; Eukaryota.
DR GeneTree; ENSGT00950000183036; -.
DR HOGENOM; CLU_020945_1_1_1; -.
DR InParanoid; Q8R4F0; -.
DR OMA; WQARRKF; -.
DR OrthoDB; 1379516at2759; -.
DR PhylomeDB; Q8R4F0; -.
DR TreeFam; TF317783; -.
DR Reactome; R-MMU-3295583; TRP channels.
DR BioGRID-ORCS; 171166; 1 hit in 71 CRISPR screens.
DR ChiTaRS; Mcoln3; mouse.
DR PRO; PR:Q8R4F0; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; Q8R4F0; protein.
DR Bgee; ENSMUSG00000036853; Expressed in vestibular membrane of cochlear duct and 106 other tissues.
DR ExpressionAtlas; Q8R4F0; baseline and differential.
DR Genevisible; Q8R4F0; MM.
DR GO; GO:0000421; C:autophagosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005765; C:lysosomal membrane; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0060171; C:stereocilium membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0072345; F:NAADP-sensitive calcium-release channel activity; IBA:GO_Central.
DR GO; GO:0042491; P:inner ear auditory receptor cell differentiation; IMP:MGI.
DR GO; GO:0007626; P:locomotory behavior; IMP:MGI.
DR InterPro; IPR039031; Mucolipin.
DR InterPro; IPR013122; PKD1_2_channel.
DR PANTHER; PTHR12127; PTHR12127; 1.
DR Pfam; PF08016; PKD_channel; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cell projection; Cytoplasmic vesicle; Disease variant;
KW Disulfide bond; Endosome; Glycoprotein; Ion channel; Ion transport;
KW Lipid-binding; Membrane; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..553
FT /note="Mucolipin-3"
FT /id="PRO_0000215368"
FT TOPO_DOM 1..62
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TRANSMEM 63..83
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TOPO_DOM 84..283
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TRANSMEM 284..304
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TOPO_DOM 305..341
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TRANSMEM 342..362
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TOPO_DOM 363..371
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TRANSMEM 372..392
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TOPO_DOM 393..414
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TRANSMEM 415..435
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TOPO_DOM 436..443
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT INTRAMEM 444..464
FT /note="Pore-forming"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TOPO_DOM 465..475
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TRANSMEM 476..497
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT TOPO_DOM 498..553
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT REGION 52..62
FT /note="Interaction with phosphoinositides"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT REGION 104..118
FT /note="Extracellular/lumenal pore loop"
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT MOTIF 456..459
FT /note="Selectivity filter"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT SITE 305
FT /note="Interaction with phosphoinositides"
FT /evidence="ECO:0000250|UniProtKB:F6RG56"
FT CARBOHYD 138
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 205
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 159..185
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT DISULFID 238..269
FT /evidence="ECO:0000250|UniProtKB:Q9GZU1"
FT VARIANT 362
FT /note="I -> T (in Va-J)"
FT /evidence="ECO:0000269|PubMed:12403827"
FT VARIANT 419
FT /note="A -> P (in Va and Va-J; constitutive active cation
FT channel localized to plasma membrane)"
FT /evidence="ECO:0000269|PubMed:12403827,
FT ECO:0000269|PubMed:17989217, ECO:0000269|PubMed:18048323"
FT MUTAGEN 458..459
FT /note="DD->KK: Abolishes channel activity."
FT /evidence="ECO:0000269|PubMed:17989217"
FT CONFLICT 193
FT /note="A -> D (in Ref. 3; BAC27146)"
FT /evidence="ECO:0000305"
FT CONFLICT 467
FT /note="M -> K (in Ref. 3; BAC27146)"
FT /evidence="ECO:0000305"
FT CONFLICT 543
FT /note="P -> A (in Ref. 3; BAC28916)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 553 AA; 63748 MW; 8E257B05D96DF536 CRC64;
MANPEVLVSS CRARQDESPC TFHPSSSPSE QLLLEDQMRR KLKFFFMNPC EKFWARGRKP
WKLAIQILKI AMVTIQLVLF GLSNQMVVAF KEENTIAFKH LFLKGYMDRM DDTYAVYTQS
EVYDQIIFAV TQYLQLQNIS VGNHAYENKG TKQSAMAICQ HFYRQGTICP GNDTFDIDPE
VETECFLVEP DEASHLGTPG ENKLNLSLDF HRLLTVELQF KLKAINLQTV RHQELPDCYD
FTLTITFDNK AHSGRIKISL DNDISIKECK DWHVSGSIQK NTHYMMIFDA FVILTCLASL
VLCARSVIRG LQLQQEFVNF FLLHYKKEVS ASDQMEFING WYIMIIISDI LTIVGSVLKM
EIQAKSLTSY DVCSILLGTS TMLVWLGVIR YLGFFAKYNL LILTLQAALP NVMRFCCCAA
MIYLGYCFCG WIVLGPYHEK FRSLNRVSEC LFSLINGDDM FSTFAKMQQK SYLVWLFSRV
YLYSFISLFI YMILSLFIAL ITDTYETIKH YQQDGFPETE LRKFIAECKD LPNSGKYRLE
DDPPGSLLCC CKK
