MREG_MOUSE
ID MREG_MOUSE Reviewed; 214 AA.
AC Q6NVG5;
DT 26-JUN-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 117.
DE RecName: Full=Melanoregulin {ECO:0000303|PubMed:17260955, ECO:0000303|PubMed:19240024};
DE AltName: Full=Dilute suppressor protein {ECO:0000303|PubMed:15550542};
DE AltName: Full=Whn-dependent transcript 2 {ECO:0000303|PubMed:19240024};
GN Name=Mreg;
GN Synonyms=Dsu {ECO:0000303|PubMed:15550542}, Gm974,
GN Wdt2 {ECO:0000303|PubMed:19240024};
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], FUNCTION, DISRUPTION PHENOTYPE, TISSUE
RP SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC STRAIN=C57BL/6J; TISSUE=Melanocyte;
RX PubMed=15550542; DOI=10.1073/pnas.0407339101;
RA O'Sullivan T.N., Wu X.S., Rachel R.A., Huang J.-D., Swing D.A.,
RA Matesic L.E., Hammer J.A. III, Copeland N.G., Jenkins N.A.;
RT "dsu functions in a MYO5A-independent pathway to suppress the coat color of
RT dilute mice.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:16831-16836(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=3410303; DOI=10.1093/genetics/119.4.933;
RA Moore K.J., Swing D.A., Rinchik E.M., Mucenski M.L., Buchberg A.M.,
RA Copeland N.G., Jenkins N.A.;
RT "The murine dilute suppressor gene dsu suppresses the coat-color phenotype
RT of three pigment mutations that alter melanocyte morphology, d, ash and
RT ln.";
RL Genetics 119:933-941(1988).
RN [4]
RP FUNCTION, INTERACTION WITH PRPH2, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=17260955; DOI=10.1021/bi061466i;
RA Boesze-Battaglia K., Song H., Sokolov M., Lillo C., Pankoski-Walker L.,
RA Gretzula C., Gallagher B., Rachel R.A., Jenkins N.A., Copeland N.G.,
RA Morris F., Jacob J., Yeagle P., Williams D.S., Damek-Poprawa M.;
RT "The tetraspanin protein peripherin-2 forms a complex with melanoregulin, a
RT putative membrane fusion regulator.";
RL Biochemistry 46:1256-1272(2007).
RN [5]
RP FUNCTION, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, AND SUBCELLULAR
RP LOCATION.
RX PubMed=19240024; DOI=10.1074/jbc.m808857200;
RA Damek-Poprawa M., Diemer T., Lopes V.S., Lillo C., Harper D.C., Marks M.S.,
RA Wu Y., Sparrow J.R., Rachel R.A., Williams D.S., Boesze-Battaglia K.;
RT "Melanoregulin (MREG) modulates lysosome function in pigment epithelial
RT cells.";
RL J. Biol. Chem. 284:10877-10889(2009).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP FUNCTION, PALMITOYLATION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 11-CYS--CYS-14; CYS-16 AND CYS-18.
RX PubMed=22940130; DOI=10.1016/j.bbrc.2012.08.064;
RA Wu X.S., Martina J.A., Hammer J.A. III;
RT "Melanoregulin is stably targeted to the melanosome membrane by
RT palmitoylation.";
RL Biochem. Biophys. Res. Commun. 426:209-214(2012).
RN [8]
RP FUNCTION, DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, INTERACTION WITH
RP RILP, AND IDENTIFICATION IN A COMPLEX WITH DCTN1 AND RILP.
RX PubMed=22275436; DOI=10.1242/jcs.094185;
RA Ohbayashi N., Maruta Y., Ishida M., Fukuda M.;
RT "Melanoregulin regulates retrograde melanosome transport through
RT interaction with the RILP-p150Glued complex in melanocytes.";
RL J. Cell Sci. 125:1508-1518(2012).
RN [9]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22753477; DOI=10.1073/pnas.1209397109;
RA Wu X.S., Masedunskas A., Weigert R., Copeland N.G., Jenkins N.A.,
RA Hammer J.A.;
RT "Melanoregulin regulates a shedding mechanism that drives melanosome
RT transfer from melanocytes to keratinocytes.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:E2101-E2109(2012).
RN [10] {ECO:0007744|PDB:6CMY}
RP STRUCTURE BY NMR OF 33-214, FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS
RP OF TYR-166; ASP-177; GLU-180 AND ASP-181.
RX PubMed=30174147; DOI=10.1016/j.str.2018.07.009;
RA Rout A.K., Wu X., Starich M.R., Strub M.P., Hammer J.A., Tjandra N.;
RT "The Structure of Melanoregulin Reveals a Role for Cholesterol Recognition
RT in the Protein's Ability to Promote Dynein Function.";
RL Structure 0:0-0(2018).
CC -!- FUNCTION: Probably functions as cargo-recognition protein that couples
CC cytoplasmic vesicles to the transport machinery (PubMed:22940130,
CC PubMed:22275436, PubMed:30174147). Plays a role in hair pigmentation, a
CC process that involves shedding of melanosome-containing vesicles from
CC melanocytes, followed by phagocytosis of the melanosome-containing
CC vesicles by keratinocytes (PubMed:15550542, PubMed:3410303,
CC PubMed:22753477). Functions on melanosomes as receptor for RILP and the
CC complex formed by RILP and DCTN1, and thereby contributes to retrograde
CC melanosome transport from the cell periphery to the center
CC (PubMed:22940130, PubMed:22275436). Overexpression causes accumulation
CC of late endosomes and/or lysosomes at the microtubule organising center
CC (MTOC) at the center of the cell (PubMed:19240024, PubMed:30174147).
CC Probably binds cholesterol and requires the presence of cholesterol in
CC membranes to function in microtubule-mediated retrograde organelle
CC transport (PubMed:30174147). Binds phosphatidylinositol 3-phosphate,
CC phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate and
CC phosphatidylinositol 3,5-bisphosphate, but not phosphatidylinositol
CC 3,4-bisphosphate or phosphatidylinositol 4,5-bisphosphate
CC (PubMed:19240024). Required for normal phagosome clearing and normal
CC activation of lysosomal enzymes in lysosomes from retinal pigment
CC epithelium cells (PubMed:19240024). Required for normal degradation of
CC the lipofuscin component N-retinylidene-N-retinylethanolamine (A2E) in
CC the eye (PubMed:19240024). May function in membrane fusion and regulate
CC the biogenesis of disk membranes of photoreceptor rod cells (Probable).
CC {ECO:0000269|PubMed:15550542, ECO:0000269|PubMed:19240024,
CC ECO:0000269|PubMed:22275436, ECO:0000269|PubMed:22753477,
CC ECO:0000269|PubMed:22940130, ECO:0000269|PubMed:30174147,
CC ECO:0000269|PubMed:3410303, ECO:0000305|PubMed:17260955}.
CC -!- SUBUNIT: Identified in a complex with RILP and DCTN1; interacts
CC directly with RILP, but does not interact directly with DCTN1
CC (PubMed:22275436). Interacts with PRPH2 (PubMed:17260955).
CC {ECO:0000269|PubMed:17260955, ECO:0000269|PubMed:22275436}.
CC -!- SUBCELLULAR LOCATION: Apical cell membrane
CC {ECO:0000269|PubMed:17260955}; Peripheral membrane protein
CC {ECO:0000269|PubMed:17260955}. Melanosome membrane
CC {ECO:0000269|PubMed:22275436, ECO:0000269|PubMed:22940130}; Lipid-
CC anchor {ECO:0000269|PubMed:22940130}. Lysosome membrane
CC {ECO:0000269|PubMed:22940130, ECO:0000269|PubMed:30174147}; Lipid-
CC anchor {ECO:0000269|PubMed:22940130}. Cytoplasmic vesicle membrane
CC {ECO:0000269|PubMed:19240024}. Note=Localizes to the inner segment and
CC basal outer segment of rods in the retina.
CC {ECO:0000269|PubMed:17260955}.
CC -!- TISSUE SPECIFICITY: Detected in melanocytes (PubMed:15550542).
CC Expressed in retina, in retinal pigment epithelium (at protein level)
CC (PubMed:17260955, PubMed:19240024). Widely expressed with higher
CC expression in skin, heart, liver, testis and thymus (PubMed:15550542).
CC Detected in retina, in retinal pigment epithelium cells
CC (PubMed:19240024). {ECO:0000269|PubMed:15550542,
CC ECO:0000269|PubMed:17260955, ECO:0000269|PubMed:19240024}.
CC -!- DEVELOPMENTAL STAGE: Detected throughout embryogenesis, from 7 dpc to
CC 17 dpc. {ECO:0000269|PubMed:15550542}.
CC -!- PTM: Palmitoylated. Palmitoylation is required to maintain the protein
CC at the melanosome membrane. {ECO:0000269|PubMed:22940130}.
CC -!- DISRUPTION PHENOTYPE: Dilute mice carry a hypomorphic allele of Myo5a,
CC resulting in melanosome clustering in the center of the cell. This
CC causes decreased light absorption and an apparent dilution of coat
CC color. The hair color of mice that are deficient for both Myo5a and
CC Mreg appears nearly normal, but the abnormal clustering of the
CC melanosomes persists (PubMed:15550542, PubMed:3410303,
CC PubMed:22753477). Likewise, mice deficient for Rab27a or Mreg have a
CC gray coat, while mice deficient for Mreg and Rab27a, or Mreg and Mlph,
CC have a hair coat that appears nearly black (PubMed:3410303). In spite
CC of melanosome clustering, shedding of melanosome-containing vesicles
CC and their uptake by adjacent keratinocytes is restored in mice that are
CC deficient for both Myo5a and Mreg (PubMed:22753477). RNAi-mediated
CC knockdown of Mreg in cultured Rab27a-deficient melanocytes restores
CC normal melanosome location at the cell periphery. In cultured wild-type
CC melanocytes melanosomes are dispersed at the cell periphery, and RNAi-
CC mediated knockdown of Mreg has no effect on melanosome location
CC (PubMed:22275436). In mice lacking Mreg, the number of phagosomes in
CC retinal pigment epithelial cells displays a normal, rapid increase
CC after the onset of light, but then decreases much more slowly than in
CC wild-type (PubMed:19240024). Eyecups from 9 and 12 month old mutant
CC mice display increased levels of the lipofuscin component N-
CC retinylidene-N-retinylethanolamine (A2E) (PubMed:19240024).
CC {ECO:0000269|PubMed:15550542, ECO:0000269|PubMed:19240024,
CC ECO:0000269|PubMed:22275436, ECO:0000269|PubMed:22753477,
CC ECO:0000269|PubMed:3410303}.
CC -!- SIMILARITY: Belongs to the melanoregulin family. {ECO:0000305}.
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DR EMBL; AY628210; AAV32092.1; -; mRNA.
DR EMBL; BC068125; AAH68125.1; -; mRNA.
DR CCDS; CCDS15032.1; -.
DR RefSeq; NP_001005423.1; NM_001005423.2.
DR PDB; 6CMY; NMR; -; A=33-214.
DR PDBsum; 6CMY; -.
DR AlphaFoldDB; Q6NVG5; -.
DR BMRB; Q6NVG5; -.
DR SMR; Q6NVG5; -.
DR STRING; 10090.ENSMUSP00000041878; -.
DR iPTMnet; Q6NVG5; -.
DR PhosphoSitePlus; Q6NVG5; -.
DR SwissPalm; Q6NVG5; -.
DR EPD; Q6NVG5; -.
DR MaxQB; Q6NVG5; -.
DR PaxDb; Q6NVG5; -.
DR PeptideAtlas; Q6NVG5; -.
DR PRIDE; Q6NVG5; -.
DR ProteomicsDB; 291399; -.
DR Antibodypedia; 34232; 182 antibodies from 20 providers.
DR DNASU; 381269; -.
DR Ensembl; ENSMUST00000048860; ENSMUSP00000041878; ENSMUSG00000039395.
DR GeneID; 381269; -.
DR KEGG; mmu:381269; -.
DR UCSC; uc007bkg.2; mouse.
DR CTD; 55686; -.
DR MGI; MGI:2151839; Mreg.
DR VEuPathDB; HostDB:ENSMUSG00000039395; -.
DR eggNOG; ENOG502S05X; Eukaryota.
DR GeneTree; ENSGT00390000008926; -.
DR HOGENOM; CLU_105265_0_0_1; -.
DR InParanoid; Q6NVG5; -.
DR OMA; CRCLEEP; -.
DR OrthoDB; 1250643at2759; -.
DR PhylomeDB; Q6NVG5; -.
DR TreeFam; TF334733; -.
DR BioGRID-ORCS; 381269; 4 hits in 73 CRISPR screens.
DR ChiTaRS; Mreg; mouse.
DR PRO; PR:Q6NVG5; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; Q6NVG5; protein.
DR Bgee; ENSMUSG00000039395; Expressed in soleus muscle and 203 other tissues.
DR Genevisible; Q6NVG5; MM.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IDA:UniProtKB.
DR GO; GO:0031300; C:intrinsic component of organelle membrane; IDA:UniProtKB.
DR GO; GO:0031902; C:late endosome membrane; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0042470; C:melanosome; IDA:MGI.
DR GO; GO:0033162; C:melanosome membrane; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:MGI.
DR GO; GO:0035091; F:phosphatidylinositol binding; IDA:UniProtKB.
DR GO; GO:0048066; P:developmental pigmentation; IMP:MGI.
DR GO; GO:0030318; P:melanocyte differentiation; IMP:MGI.
DR GO; GO:0032400; P:melanosome localization; IMP:UniProtKB.
DR GO; GO:0032402; P:melanosome transport; IDA:MGI.
DR GO; GO:0072385; P:minus-end-directed organelle transport along microtubule; IMP:UniProtKB.
DR GO; GO:0090382; P:phagosome maturation; IMP:UniProtKB.
DR GO; GO:0043473; P:pigmentation; IMP:MGI.
DR InterPro; IPR031638; Melanoregulin.
DR PANTHER; PTHR34340; PTHR34340; 1.
DR Pfam; PF15812; MREG; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Cytoplasmic vesicle; Lipid-binding;
KW Lipoprotein; Lysosome; Membrane; Palmitate; Phosphoprotein;
KW Reference proteome; Transport.
FT CHAIN 1..214
FT /note="Melanoregulin"
FT /id="PRO_0000292176"
FT MOTIF 162..172
FT /note="Cholesterol-binding sequence motif"
FT /evidence="ECO:0000305|PubMed:30174147"
FT MOD_RES 213
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N565"
FT MUTAGEN 2
FT /note="G->A: No effect on location at the melanosome
FT membrane."
FT /evidence="ECO:0000269|PubMed:22940130"
FT MUTAGEN 11..14
FT /note="CCCC->SSSS: Loss of location at the melanosome
FT membrane; when associated with S-16 and S-18."
FT /evidence="ECO:0000269|PubMed:22940130"
FT MUTAGEN 16
FT /note="C->S: Loss of location at the melanosome membrane;
FT when associated with 11-SSSS-14 and S-18."
FT /evidence="ECO:0000269|PubMed:22940130"
FT MUTAGEN 18
FT /note="C->S: Loss of location at the melanosome membrane;
FT when associated with 11-SSSS-14 and S-16."
FT /evidence="ECO:0000269|PubMed:22940130"
FT MUTAGEN 166
FT /note="Y->I: Loss of the ability to promote lysosome
FT clustering at the center of the cell. No effect on location
FT at lysosome membranes."
FT /evidence="ECO:0000269|PubMed:30174147"
FT MUTAGEN 177
FT /note="D->K: Mildly reduced ability to promote lysosome
FT clustering at the center of the cell; when associated with
FT K-180 and K-181."
FT /evidence="ECO:0000269|PubMed:30174147"
FT MUTAGEN 180
FT /note="E->K: Mildly reduced ability to promote lysosome
FT clustering at the center of the cell; when associated with
FT K-177 and K-181."
FT /evidence="ECO:0000269|PubMed:30174147"
FT MUTAGEN 181
FT /note="D->K: Mildly reduced ability to promote lysosome
FT clustering at the center of the cell; when associated with
FT K-177 and K-180."
FT /evidence="ECO:0000269|PubMed:30174147"
FT HELIX 55..59
FT /evidence="ECO:0007829|PDB:6CMY"
FT HELIX 65..79
FT /evidence="ECO:0007829|PDB:6CMY"
FT HELIX 85..115
FT /evidence="ECO:0007829|PDB:6CMY"
FT HELIX 118..125
FT /evidence="ECO:0007829|PDB:6CMY"
FT HELIX 141..152
FT /evidence="ECO:0007829|PDB:6CMY"
FT HELIX 164..174
FT /evidence="ECO:0007829|PDB:6CMY"
FT HELIX 180..189
FT /evidence="ECO:0007829|PDB:6CMY"
SQ SEQUENCE 214 AA; 25010 MW; 07537592C78CF050 CRC64;
MGLRRWLRSA CCCCPCRCLE EPARPEKEPL VSGNNPYSSF GATLERDDEK NLWSMPHDVS
HTEADDDRIL YNLIVIRNQQ TKDSEEWQRL NYDIYTLRQI RREVRNRWRR ILEDLGFQRE
ADSLLSVTKL STMSDSKNTR KAREMLLKLA EETSIFPASW ELSERYLLVV DRLIALDAAE
DFFKIASQMY PKKPGVPCLV DGQRKLHCLP FPSP
