MFS12_HUMAN
ID MFS12_HUMAN Reviewed; 480 AA.
AC Q6NUT3; A8MXP7; D6W615; E9PAJ8; Q8N459;
DT 06-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 06-FEB-2007, sequence version 2.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=Major facilitator superfamily domain-containing protein 12 {ECO:0000305};
GN Name=MFSD12 {ECO:0000303|PubMed:29025994, ECO:0000312|HGNC:HGNC:28299};
GN Synonyms=C19orf28 {ECO:0000312|HGNC:HGNC:28299};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, Hypothalamus, and Skin;
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 [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [5]
RP ACETYLATION AT MET-1.
RX PubMed=25732826; DOI=10.1016/j.celrep.2015.01.053;
RA Aksnes H., Van Damme P., Goris M., Starheim K.K., Marie M., Stoeve S.I.,
RA Hoel C., Kalvik T.V., Hole K., Glomnes N., Furnes C., Ljostveit S.,
RA Ziegler M., Niere M., Gevaert K., Arnesen T.;
RT "An organellar nalpha-acetyltransferase, naa60, acetylates cytosolic N
RT termini of transmembrane proteins and maintains Golgi integrity.";
RL Cell Rep. 10:1362-1374(2015).
RN [6]
RP SUBCELLULAR LOCATION, AND POLYMORPHISM.
RX PubMed=29025994; DOI=10.1126/science.aan8433;
RG NISC Comparative Sequencing Program;
RA Crawford N.G., Kelly D.E., Hansen M.E.B., Beltrame M.H., Fan S.,
RA Bowman S.L., Jewett E., Ranciaro A., Thompson S., Lo Y., Pfeifer S.P.,
RA Jensen J.D., Campbell M.C., Beggs W., Hormozdiari F., Mpoloka S.W.,
RA Mokone G.G., Nyambo T., Meskel D.W., Belay G., Haut J., Rothschild H.,
RA Zon L., Zhou Y., Kovacs M.A., Xu M., Zhang T., Bishop K., Sinclair J.,
RA Rivas C., Elliot E., Choi J., Li S.A., Hicks B., Burgess S., Abnet C.,
RA Watkins-Chow D.E., Oceana E., Song Y.S., Eskin E., Brown K.M., Marks M.S.,
RA Loftus S.K., Pavan W.J., Yeager M., Chanock S., Tishkoff S.A.;
RT "Loci associated with skin pigmentation identified in African
RT populations.";
RL Science 358:0-0(2017).
RN [7]
RP POLYMORPHISM, AND VARIANT HIS-182.
RX PubMed=30664655; DOI=10.1038/s41467-018-08147-0;
RA Adhikari K., Mendoza-Revilla J., Sohail A., Fuentes-Guajardo M.,
RA Lampert J., Chacon-Duque J.C., Hurtado M., Villegas V., Granja V.,
RA Acuna-Alonzo V., Jaramillo C., Arias W., Lozano R.B., Everardo P.,
RA Gomez-Valdes J., Villamil-Ramirez H., Silva de Cerqueira C.C.,
RA Hunemeier T., Ramallo V., Schuler-Faccini L., Salzano F.M.,
RA Gonzalez-Jose R., Bortolini M.C., Canizales-Quinteros S., Gallo C.,
RA Poletti G., Bedoya G., Rothhammer F., Tobin D.J., Fumagalli M., Balding D.,
RA Ruiz-Linares A.;
RT "A GWAS in Latin Americans highlights the convergent evolution of lighter
RT skin pigmentation in Eurasia.";
RL Nat. Commun. 10:358-358(2019).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND
RP MUTAGENESIS OF 256-LEU-LEU-257.
RX PubMed=33208952; DOI=10.1038/s41586-020-2937-x;
RA Adelmann C.H., Traunbauer A.K., Chen B., Condon K.J., Chan S.H.,
RA Kunchok T., Lewis C.A., Sabatini D.M.;
RT "MFSD12 mediates the import of cysteine into melanosomes and lysosomes.";
RL Nature 588:699-704(2020).
CC -!- FUNCTION: Transporter that mediates the import of cysteine into
CC melanosomes, thereby regulating skin pigmentation (PubMed:33208952). In
CC melanosomes, cysteine import is required both for normal levels of
CC cystine, the oxidized dimer of cysteine, and provide cysteine for the
CC production of the cysteinyldopas used in pheomelanin synthesis, thereby
CC regulating skin pigmentation (PubMed:33208952). Also catalyzes import
CC of cysteine into lysosomes in non-pigmented cells (PubMed:33208952).
CC {ECO:0000269|PubMed:33208952}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-cysteine(in) = L-cysteine(out); Xref=Rhea:RHEA:29655,
CC ChEBI:CHEBI:35235; Evidence={ECO:0000269|PubMed:33208952};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:29656;
CC Evidence={ECO:0000269|PubMed:33208952};
CC -!- INTERACTION:
CC Q6NUT3-2; P11912: CD79A; NbExp=3; IntAct=EBI-17295698, EBI-7797864;
CC Q6NUT3-2; Q8WWF3: SSMEM1; NbExp=3; IntAct=EBI-17295698, EBI-17280858;
CC Q6NUT3-2; Q9NUH8: TMEM14B; NbExp=3; IntAct=EBI-17295698, EBI-8638294;
CC -!- SUBCELLULAR LOCATION: Melanosome membrane
CC {ECO:0000269|PubMed:33208952}; Multi-pass membrane protein
CC {ECO:0000255}. Lysosome membrane {ECO:0000269|PubMed:29025994,
CC ECO:0000269|PubMed:33208952}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q6NUT3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6NUT3-2; Sequence=VSP_022779;
CC Name=3;
CC IsoId=Q6NUT3-3; Sequence=VSP_047665;
CC Name=4;
CC IsoId=Q6NUT3-4; Sequence=VSP_047666;
CC -!- TISSUE SPECIFICITY: Widely expressed, with high expression in primary
CC melanocytes. {ECO:0000269|PubMed:29025994,
CC ECO:0000269|PubMed:33208952}.
CC -!- POLYMORPHISM: Genetic variants in MFSD12 cause skin pigmentation
CC variation (PubMed:29025994, PubMed:30664655). Skin pigmentation is
CC among the most visible examples of human phenotypic variation, with a
CC broad normal range that is subject to substantial geographic
CC stratification (PubMed:29025994, PubMed:30664655). In the case of skin,
CC individuals tend to have lighter pigmentation with increasing distance
CC from the equator (PubMed:29025994, PubMed:30664655). His-192 is
CC commonly found in East Asians and Native Americans only, and
CC significantly correlates with lower solar radiation intensity in East
CC Asia (PubMed:30664655). {ECO:0000269|PubMed:29025994,
CC ECO:0000269|PubMed:30664655}.
CC -!- SIMILARITY: Belongs to the major facilitator superfamily.
CC {ECO:0000305}.
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DR EMBL; AC005786; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC005787; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471139; EAW69309.1; -; Genomic_DNA.
DR EMBL; CH471139; EAW69311.1; -; Genomic_DNA.
DR EMBL; BC036706; AAH36706.1; -; mRNA.
DR EMBL; BC068439; AAH68439.1; -; mRNA.
DR CCDS; CCDS42465.1; -. [Q6NUT3-1]
DR CCDS; CCDS74256.1; -. [Q6NUT3-2]
DR RefSeq; NP_001274458.1; NM_001287529.1. [Q6NUT3-2]
DR RefSeq; NP_778148.2; NM_174983.4. [Q6NUT3-1]
DR RefSeq; XP_006722710.1; XM_006722647.3. [Q6NUT3-3]
DR RefSeq; XP_011525986.1; XM_011527684.2. [Q6NUT3-4]
DR AlphaFoldDB; Q6NUT3; -.
DR SMR; Q6NUT3; -.
DR BioGRID; 125979; 32.
DR IntAct; Q6NUT3; 10.
DR MINT; Q6NUT3; -.
DR STRING; 9606.ENSP00000347583; -.
DR TCDB; 2.A.2.7.3; the glycoside-pentoside-hexuronide (gph):cation symporter family.
DR GlyGen; Q6NUT3; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q6NUT3; -.
DR PhosphoSitePlus; Q6NUT3; -.
DR SwissPalm; Q6NUT3; -.
DR BioMuta; MFSD12; -.
DR DMDM; 125991816; -.
DR EPD; Q6NUT3; -.
DR jPOST; Q6NUT3; -.
DR MassIVE; Q6NUT3; -.
DR MaxQB; Q6NUT3; -.
DR PaxDb; Q6NUT3; -.
DR PeptideAtlas; Q6NUT3; -.
DR PRIDE; Q6NUT3; -.
DR ProteomicsDB; 19029; -.
DR ProteomicsDB; 2337; -.
DR ProteomicsDB; 66712; -. [Q6NUT3-1]
DR ProteomicsDB; 66713; -. [Q6NUT3-2]
DR Antibodypedia; 23242; 68 antibodies from 17 providers.
DR DNASU; 126321; -.
DR Ensembl; ENST00000355415.7; ENSP00000347583.1; ENSG00000161091.14. [Q6NUT3-1]
DR Ensembl; ENST00000389395.7; ENSP00000374046.3; ENSG00000161091.14. [Q6NUT3-2]
DR Ensembl; ENST00000588918.5; ENSP00000467207.1; ENSG00000161091.14. [Q6NUT3-2]
DR GeneID; 126321; -.
DR KEGG; hsa:126321; -.
DR MANE-Select; ENST00000355415.7; ENSP00000347583.1; NM_174983.5; NP_778148.2.
DR UCSC; uc002lxz.5; human. [Q6NUT3-1]
DR CTD; 126321; -.
DR DisGeNET; 126321; -.
DR GeneCards; MFSD12; -.
DR HGNC; HGNC:28299; MFSD12.
DR HPA; ENSG00000161091; Low tissue specificity.
DR MIM; 617745; gene.
DR neXtProt; NX_Q6NUT3; -.
DR OpenTargets; ENSG00000161091; -.
DR PharmGKB; PA134955537; -.
DR VEuPathDB; HostDB:ENSG00000161091; -.
DR eggNOG; KOG4830; Eukaryota.
DR GeneTree; ENSGT00390000005318; -.
DR HOGENOM; CLU_030068_1_0_1; -.
DR InParanoid; Q6NUT3; -.
DR OMA; MAMVPEL; -.
DR OrthoDB; 605453at2759; -.
DR PhylomeDB; Q6NUT3; -.
DR TreeFam; TF314080; -.
DR PathwayCommons; Q6NUT3; -.
DR SignaLink; Q6NUT3; -.
DR BioGRID-ORCS; 126321; 20 hits in 1074 CRISPR screens.
DR ChiTaRS; MFSD12; human.
DR GenomeRNAi; 126321; -.
DR Pharos; Q6NUT3; Tbio.
DR PRO; PR:Q6NUT3; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q6NUT3; protein.
DR Bgee; ENSG00000161091; Expressed in stromal cell of endometrium and 157 other tissues.
DR ExpressionAtlas; Q6NUT3; baseline and differential.
DR Genevisible; Q6NUT3; HS.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005770; C:late endosome; IDA:CACAO.
DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0042470; C:melanosome; IDA:UniProtKB.
DR GO; GO:0033162; C:melanosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0033229; F:cysteine transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015293; F:symporter activity; IEA:InterPro.
DR GO; GO:0008643; P:carbohydrate transport; IEA:InterPro.
DR GO; GO:1903712; P:cysteine transmembrane transport; IDA:UniProtKB.
DR GO; GO:0042438; P:melanin biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0048022; P:negative regulation of melanin biosynthetic process; IEA:Ensembl.
DR GO; GO:0071702; P:organic substance transport; IBA:GO_Central.
DR GO; GO:0043474; P:pigment metabolic process involved in pigmentation; IMP:UniProtKB.
DR GO; GO:0048021; P:regulation of melanin biosynthetic process; IMP:UniProtKB.
DR Gene3D; 1.20.1250.20; -; 2.
DR InterPro; IPR039672; MFS_2.
DR InterPro; IPR036259; MFS_trans_sf.
DR PANTHER; PTHR11328; PTHR11328; 1.
DR SUPFAM; SSF103473; SSF103473; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Amino-acid transport; Lysosome;
KW Melanin biosynthesis; Membrane; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..480
FT /note="Major facilitator superfamily domain-containing
FT protein 12"
FT /id="PRO_0000274522"
FT TRANSMEM 27..47
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 57..77
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 98..118
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 125..145
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 171..191
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 219..239
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 280..302
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 311..331
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 348..368
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 369..389
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 403..423
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 447..467
FT /note="Helical"
FT /evidence="ECO:0000255"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000269|PubMed:25732826"
FT VAR_SEQ 92..100
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_022779"
FT VAR_SEQ 474..480
FT /note="WDRDARP -> SFLAWRRGRGEDKGPGYSWIPTVLVQPPRPTSPFLWEAPLA
FT WRCTRKKWSGAGTKPWPREDWGTH (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_047665"
FT VAR_SEQ 474..480
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000305"
FT /id="VSP_047666"
FT VARIANT 182
FT /note="Y -> H (influences skin pigmentation;
FT dbSNP:rs2240751)"
FT /evidence="ECO:0000269|PubMed:30664655"
FT /id="VAR_030309"
FT VARIANT 203
FT /note="I -> V (in dbSNP:rs34562175)"
FT /id="VAR_050300"
FT VARIANT 243
FT /note="R -> H (in dbSNP:rs10414812)"
FT /id="VAR_030310"
FT VARIANT 395
FT /note="G -> S (in dbSNP:rs34878396)"
FT /id="VAR_050301"
FT VARIANT 476
FT /note="R -> C (in dbSNP:rs7252640)"
FT /id="VAR_030311"
FT MUTAGEN 256..257
FT /note="LL->AA: Reduced localization to lysosomes and
FT redirection to the cell membrane."
FT /evidence="ECO:0000269|PubMed:33208952"
FT CONFLICT 441
FT /note="F -> L (in Ref. 3; AAH68439)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 480 AA; 52075 MW; 8F995556BE29E8C1 CRC64;
MGPGPPAAGA APSPRPLSLV ARLSYAVGHF LNDLCASMWF TYLLLYLHSV RAYSSRGAGL
LLLLGQVADG LCTPLVGYEA DRAASCCARY GPRKAWHLVG TVCVLLSFPF IFSPCLGCGA
ATPEWAALLY YGPFIVIFQF GWASTQISHL SLIPELVTND HEKVELTALR YAFTVVANIT
VYGAAWLLLH LQGSSRVEPT QDISISDQLG GQDVPVFRNL SLLVVGVGAV FSLLFHLGTR
ERRRPHAEEP GEHTPLLAPA TAQPLLLWKH WLREPAFYQV GILYMTTRLI VNLSQTYMAM
YLTYSLHLPK KFIATIPLVM YLSGFLSSFL MKPINKCIGR NMTYFSGLLV ILAFAAWVAL
AEGLGVAVYA AAVLLGAGCA TILVTSLAMT ADLIGPHTNS GAFVYGSMSF LDKVANGLAV
MAIQSLHPCP SELCCRACVS FYHWAMVAVT GGVGVAAALC LCSLLLWPTR LRRWDRDARP
