MCLN3_CALJA
ID MCLN3_CALJA Reviewed; 553 AA.
AC F6RG56;
DT 20-DEC-2017, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 1.
DT 03-AUG-2022, entry version 54.
DE RecName: Full=Mucolipin-3;
DE AltName: Full=Transient receptor potential channel mucolipin 3;
DE Short=TRPML3;
GN Name=MCOLN3 {ECO:0000312|EMBL:JAB18777.1,
GN ECO:0000312|Ensembl:ENSCJAP00000012762};
OS Callithrix jacchus (White-tufted-ear marmoset).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Platyrrhini; Cebidae;
OC Callitrichinae; Callithrix; Callithrix.
OX NCBI_TaxID=9483 {ECO:0000312|Proteomes:UP000008225};
RN [1] {ECO:0000312|EMBL:JAB18777.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Hippocampus {ECO:0000312|EMBL:JAB18777.1};
RX PubMed=25243066; DOI=10.1186/2047-217x-3-14;
RA Maudhoo M.D., Ren D., Gradnigo J.S., Gibbs R.M., Lubker A.C.,
RA Moriyama E.N., French J.A., Norgren R.B. Jr.;
RT "De novo assembly of the common marmoset transcriptome from NextGen mRNA
RT sequences.";
RL Gigascience 3:14-14(2014).
RN [2] {ECO:0000312|Ensembl:ENSCJAP00000012762, ECO:0000312|Proteomes:UP000008225}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Warren W., Ye L., Minx P., Worley K., Gibbs R., Wilson R.K.;
RL Submitted (MAR-2009) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.94 ANGSTROMS) OF MUTANT GLN-138,
RP FUNCTION, ACTIVITY REGULATION, TOPOLOGY, SUBUNIT, AND MUTAGENESIS OF
RP LYS-52; ARG-58; LYS-62; ASN-138; ARG-305; ALA-419 AND PHE-524.
RX PubMed=29019979; DOI=10.1038/nature24055;
RA Hirschi M., Herzik M.A. Jr., Wie J., Suo Y., Borschel W.F., Ren D.,
RA Lander G.C., Lee S.Y.;
RT "Cryo-electron microscopy structure of the lysosomal calcium-permeable
RT channel TRPML3.";
RL Nature 550:411-414(2017).
CC -!- FUNCTION: Nonselective ligand-gated cation channel probably playing a
CC role in the regulation of membrane trafficking events
CC (PubMed:29019979). Acts as Ca(2+)-permeable cation channel with
CC inwardly rectifying activity (By similarity). Mediates release of
CC Ca(2+) from endosomes to the cytoplasm, contributes to endosomal
CC acidification and is involved in the regulation of membrane trafficking
CC and fusion in the endosomal pathway (By similarity). Does not seem to
CC act as mechanosensory transduction channel in inner ear sensory hair
CC cells. Proposed to play a critical role at the cochlear stereocilia
CC ankle-link region during hair-bundle growth. Involved in the regulation
CC of autophagy. Through association with GABARAPL2 may be involved in
CC autophagosome formation possibly providing Ca(2+) for the fusion
CC process (By similarity). 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:Q8R4F0,
CC ECO:0000250|UniProtKB:Q8TDD5}.
CC -!- ACTIVITY REGULATION: Channel activity is activated by PtdIns(3,5)P2
CC (phosphatidylinositol 3,5-bisphosphate) (PubMed:29019979). Inhibited by
CC lumenal H(+) and Na(+). The channel pore shows dynamic behavior and
CC undergoes spontaneous, Ca(2+)-dependent modulation when conducting
CC Ca(2+). {ECO:0000250|UniProtKB:Q8TDD5, ECO:0000269|PubMed:29019979}.
CC -!- SUBUNIT: Homotetramer (PubMed:29019979). Can heterooligomerize with
CC MCOLN1; heteromeric assemblies have different channel properties as
CC compared to the respective homooligomers and may be tissue-specific.
CC May heterooligomerize with TRPV5 to form a functional distinct ion
CC channel (By similarity). Interacts with GABARAPL2 (By similarity).
CC {ECO:0000250|UniProtKB:Q8R4F0, ECO:0000250|UniProtKB:Q8TDD5,
CC ECO:0000269|PubMed:29019979}.
CC -!- INTERACTION:
CC F6RG56; F6RG56: MCOLN3; NbExp=9; IntAct=EBI-26372251, EBI-26372251;
CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:29019979};
CC Multi-pass membrane protein {ECO:0000269|PubMed:29019979}. Early
CC endosome membrane {ECO:0000250|UniProtKB:Q8TDD5}; Multi-pass membrane
CC protein {ECO:0000269|PubMed:29019979}. Late endosome membrane
CC {ECO:0000250|UniProtKB:Q8R4F0}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:29019979}. Cytoplasmic vesicle, autophagosome
CC membrane {ECO:0000250|UniProtKB:Q8R4F0}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:29019979}. Cell projection, stereocilium membrane
CC {ECO:0000250|UniProtKB:Q8R4F0}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:29019979}. 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 (By similarity).
CC {ECO:0000250|UniProtKB:Q8R4F0, ECO:0000250|UniProtKB:Q8TDD5}.
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 -!- SIMILARITY: Belongs to the transient receptor (TC 1.A.4) family.
CC Polycystin subfamily. MCOLN3 sub-subfamily. {ECO:0000305}.
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DR EMBL; GAMS01004359; JAB18777.1; -; mRNA.
DR EMBL; ACFV01092212; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; ACFV01092213; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; XP_002751067.1; XM_002751021.3.
DR RefSeq; XP_008999856.1; XM_009001608.2.
DR PDB; 5W3S; EM; 2.94 A; A/B/C/D=1-553.
DR PDBsum; 5W3S; -.
DR AlphaFoldDB; F6RG56; -.
DR SMR; F6RG56; -.
DR STRING; 9483.ENSCJAP00000012762; -.
DR Ensembl; ENSCJAT00000013447; ENSCJAP00000012762; ENSCJAG00000007003.
DR GeneID; 100412379; -.
DR KEGG; cjc:100412379; -.
DR CTD; 55283; -.
DR eggNOG; KOG3733; Eukaryota.
DR GeneTree; ENSGT01030000234635; -.
DR HOGENOM; CLU_020945_1_1_1; -.
DR InParanoid; F6RG56; -.
DR OMA; WQARRKF; -.
DR OrthoDB; 1379516at2759; -.
DR TreeFam; TF317783; -.
DR Proteomes; UP000008225; Chromosome 7.
DR Bgee; ENSCJAG00000006859; Expressed in testis and 3 other tissues.
DR GO; GO:0000421; C:autophagosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:1905103; C:integral component of lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IDA:UniProtKB.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0060171; C:stereocilium membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0097682; F:intracellular phosphatidylinositol-3,5-bisphosphate-sensitive cation channel activity; IDA:UniProtKB.
DR GO; GO:0080025; F:phosphatidylinositol-3,5-bisphosphate binding; IDA:UniProtKB.
DR GO; GO:0098655; P:cation transmembrane transport; IDA:UniProtKB.
DR GO; GO:0051289; P:protein homotetramerization; IDA:UniProtKB.
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 3D-structure; Cell membrane; Cell projection; Cytoplasmic vesicle;
KW Disulfide bond; Endosome; Glycoprotein; Ion channel; Ion transport;
KW Lipid-binding; Lysosome; Membrane; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..553
FT /note="Mucolipin-3"
FT /id="PRO_0000442777"
FT TOPO_DOM 1..62
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TRANSMEM 63..83
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TOPO_DOM 84..283
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TRANSMEM 284..304
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TOPO_DOM 305..341
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TRANSMEM 342..362
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TOPO_DOM 363..371
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TRANSMEM 372..392
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TOPO_DOM 393..414
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TRANSMEM 415..435
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TOPO_DOM 436..443
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29019979"
FT INTRAMEM 444..464
FT /note="Pore-forming"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TOPO_DOM 465..475
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TRANSMEM 476..497
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:29019979"
FT TOPO_DOM 498..553
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:29019979"
FT REGION 52..62
FT /note="Interaction with phosphoinositides"
FT /evidence="ECO:0000269|PubMed:29019979"
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:0000269|PubMed:29019979"
FT SITE 305
FT /note="Interaction with phosphoinositides"
FT /evidence="ECO:0000269|PubMed:29019979"
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 MUTAGEN 52
FT /note="K->A: Loss of phosphatidylinositol 3,5-bisphosphate
FT binding; when associated with A-58 and A-62."
FT /evidence="ECO:0000269|PubMed:29019979"
FT MUTAGEN 58
FT /note="R->A: Abolishes channel activation by
FT phosphatidylinositol 3,5-bisphosphate. Loss of
FT phosphatidylinositol 3,5-bisphosphate binding; when
FT associated with A-52 and A-62."
FT /evidence="ECO:0000269|PubMed:29019979"
FT MUTAGEN 62
FT /note="K->A: Loss of phosphatidylinositol 3,5-bisphosphate
FT binding; when associated with A-52 and A-58."
FT /evidence="ECO:0000269|PubMed:29019979"
FT MUTAGEN 138
FT /note="N->Q: Loss of a predicted N-glycosylation site. No
FT effect on function."
FT /evidence="ECO:0000269|PubMed:29019979"
FT MUTAGEN 305
FT /note="R->A: Abolishes channel activation by
FT phosphatidylinositol 3,5-bisphosphate."
FT /evidence="ECO:0000269|PubMed:29019979"
FT MUTAGEN 419
FT /note="A->P: Constitutively active channel."
FT /evidence="ECO:0000269|PubMed:29019979"
FT MUTAGEN 524
FT /note="F->A: Decreases channel activation by
FT phosphatidylinositol 3,5-bisphosphate."
FT /evidence="ECO:0000269|PubMed:29019979"
FT HELIX 34..46
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 51..54
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 61..102
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 119..134
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 136..139
FT /evidence="ECO:0007829|PDB:5W3S"
FT STRAND 156..169
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 170..172
FT /evidence="ECO:0007829|PDB:5W3S"
FT STRAND 174..188
FT /evidence="ECO:0007829|PDB:5W3S"
FT STRAND 210..212
FT /evidence="ECO:0007829|PDB:5W3S"
FT STRAND 215..225
FT /evidence="ECO:0007829|PDB:5W3S"
FT STRAND 227..229
FT /evidence="ECO:0007829|PDB:5W3S"
FT STRAND 238..248
FT /evidence="ECO:0007829|PDB:5W3S"
FT STRAND 256..267
FT /evidence="ECO:0007829|PDB:5W3S"
FT STRAND 272..274
FT /evidence="ECO:0007829|PDB:5W3S"
FT STRAND 277..279
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 285..325
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 332..337
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 340..365
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 372..390
FT /evidence="ECO:0007829|PDB:5W3S"
FT TURN 391..394
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 396..434
FT /evidence="ECO:0007829|PDB:5W3S"
FT STRAND 438..440
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 444..455
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 461..465
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 472..491
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 494..514
FT /evidence="ECO:0007829|PDB:5W3S"
FT HELIX 522..525
FT /evidence="ECO:0007829|PDB:5W3S"
SQ SEQUENCE 553 AA; 64085 MW; 09C0231CADF07AC3 CRC64;
MANPEIVISS CSSHEEENRC NFNQHTSPSE ELLLEDQMRR KLKFFFMNPC EKFWARGRKP
WKLAIQILKI AMVTIQLVLF GLSNQMVVAF KEENTVAFKH LFLKGYIDRM DDTYAVYTQS
DVYDQIIFAV NQYLQLYNVS VGNHAYENKG TDQSAMAICQ HFYKRGNIYP GNDTFDIDPE
IETDCFFVEP DEPFHIGTPA ENKLNLTLDF HRLLTVELQF KLKAINLQTV RHQELPDCYD
FTLTITFDNK AHSGRIKISL DNDISIRECK DWHVSGSIQK NTHNMMIFDA FVILTCLVSL
ILCIRSVISG LQLQQEFVNF FLLHYKKDVS VSDQMEFVNG WYIMIIISDI LTIIGSILKM
EIQAKSLTSY DVCSILLGTS TMLVWLGVIR YLGFFAKYNL LILTLQAALP NVIRFCCCAA
MIYLGYCFCG WIVLGPYHNK FRSLNMVSEC LFSLINGDDM FATFAKMQQK SYLVWLFSRI
YLYSFISLFI YMILSLFIAL ITDTYETIKH YQQDGFPETE LRTFISECKD LPNSGKFRLE
DDPPVSLFCC CKK
