ID   MRAP_HUMAN              Reviewed;         172 AA.
AC   Q8TCY5; Q5EBR3; Q8TDB7; Q8WXC1; Q8WXC2;
DT   19-SEP-2002, integrated into UniProtKB/Swiss-Prot.
DT   17-OCT-2006, sequence version 2.
DT   24-JAN-2024, entry version 163.
DE   RecName: Full=Melanocortin-2 receptor accessory protein;
DE   AltName: Full=B27;
DE   AltName: Full=Fat cell-specific low molecular weight protein;
DE   AltName: Full=Fat tissue-specific low MW protein;
GN   Name=MRAP; Synonyms=C21orf61, FALP;
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 [MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Adipocyte;
RX   PubMed=12054497; DOI=10.1016/s0006-291x(02)00354-6;
RA   Xu A., Choi K.-L., Wang Y., Permana P.A., Xu L.Y., Bogardus C.,
RA   Cooper G.J.S.;
RT   "Identification of novel putative membrane proteins selectively expressed
RT   during adipose conversion of 3T3-L1 cells.";
RL   Biochem. Biophys. Res. Commun. 293:1161-1167(2002).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4).
RC   TISSUE=Brain;
RX   PubMed=12036298; DOI=10.1006/geno.2002.6782;
RA   Gardiner K., Slavov D., Bechtel L., Davisson M.;
RT   "Annotation of human chromosome 21 for relevance to Down syndrome: gene
RT   structure and expression analysis.";
RL   Genomics 79:833-843(2002).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC   TISSUE=Thyroid;
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   FUNCTION, SUBUNIT, AND INTERACTION WITH MC1R; MC2R; MC3R; MC4R; MC5R AND
RP   MRAP2.
RX   PubMed=19329486; DOI=10.1073/pnas.0809918106;
RA   Chan L.F., Webb T.R., Chung T.T., Meimaridou E., Cooray S.N., Guasti L.,
RA   Chapple J.P., Egertova M., Elphick M.R., Cheetham M.E., Metherell L.A.,
RA   Clark A.J.;
RT   "MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor
RT   family.";
RL   Proc. Natl. Acad. Sci. U.S.A. 106:6146-6151(2009).
RN   [5]
RP   FUNCTION, SUBUNIT, TOPOLOGY, AND INTERACTION WITH MC2R AND MRAP2.
RX   PubMed=20371771; DOI=10.1126/scisignal.2000593;
RA   Sebag J.A., Hinkle P.M.;
RT   "Regulation of G protein-coupled receptor signaling: specific dominant-
RT   negative effects of melanocortin 2 receptor accessory protein 2.";
RL   Sci. Signal. 3:RA28-RA28(2010).
RN   [6]
RP   INVOLVEMENT IN GCCD2, FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP   AND INTERACTION WITH MC2R.
RX   PubMed=15654338; DOI=10.1038/ng1501;
RA   Metherell L.A., Chapple J.P., Cooray S., David A., Becker C.,
RA   Rueschendorf F., Naville D., Begeot M., Khoo B., Nuernberg P., Huebner A.,
RA   Cheetham M.E., Clark A.J.L.;
RT   "Mutations in MRAP, encoding a new interacting partner of the ACTH
RT   receptor, cause familial glucocorticoid deficiency type 2.";
RL   Nat. Genet. 37:166-170(2005).
CC   -!- FUNCTION: Modulator of melanocortin receptors (MC1R, MC2R, MC3R, MC4R
CC       and MC5R). Acts by increasing ligand-sensitivity of melanocortin
CC       receptors and enhancing generation of cAMP by the receptors. Required
CC       both for MC2R trafficking to the cell surface of adrenal cells and for
CC       signaling in response to corticotropin (ACTH). May be involved in the
CC       intracellular trafficking pathways in adipocyte cells.
CC       {ECO:0000269|PubMed:15654338, ECO:0000269|PubMed:19329486,
CC       ECO:0000269|PubMed:20371771}.
CC   -!- SUBUNIT: Homodimer and heterodimer. Forms antiparallel homodimers and
CC       heterodimers with MRAP2. Interacts with MC1R, MC2R, MC3R, MC4R and
CC       MC5R. {ECO:0000269|PubMed:15654338, ECO:0000269|PubMed:19329486,
CC       ECO:0000269|PubMed:20371771}.
CC   -!- INTERACTION:
CC       Q8TCY5; P28329-3: CHAT; NbExp=3; IntAct=EBI-9538727, EBI-25837549;
CC       Q8TCY5; P22607: FGFR3; NbExp=3; IntAct=EBI-9538727, EBI-348399;
CC       Q8TCY5; Q01726: MC1R; NbExp=2; IntAct=EBI-9538727, EBI-9538513;
CC       Q8TCY5; Q01718: MC2R; NbExp=3; IntAct=EBI-9538727, EBI-9537171;
CC       Q8TCY5; P41968: MC3R; NbExp=2; IntAct=EBI-9538727, EBI-9538510;
CC       Q8TCY5; P32245: MC4R; NbExp=2; IntAct=EBI-9538727, EBI-3910694;
CC       Q8TCY5; P33032: MC5R; NbExp=2; IntAct=EBI-9538727, EBI-9538507;
CC       Q8TCY5; Q8TCY5: MRAP; NbExp=2; IntAct=EBI-9538727, EBI-9538727;
CC       Q8TCY5; Q96G30: MRAP2; NbExp=3; IntAct=EBI-9538727, EBI-9537218;
CC       Q8TCY5-1; Q01718: MC2R; NbExp=3; IntAct=EBI-21991233, EBI-9537171;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15654338};
CC       Single-pass membrane protein {ECO:0000269|PubMed:15654338}. Endoplasmic
CC       reticulum membrane {ECO:0000269|PubMed:15654338}; Single-pass membrane
CC       protein {ECO:0000269|PubMed:15654338}. Note=The formation of
CC       antiparallel homo- and heterodimers suggest that N- and C-terminus can
CC       both localize in the cytoplasmic and extracellular parts, depending on
CC       the context (PubMed:20371771). Upon insulin stimulation, it is
CC       redistributed into spotty structures throughout the cytoplasm.
CC       {ECO:0000269|PubMed:20371771}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=4;
CC       Name=4;
CC         IsoId=Q8TCY5-4; Sequence=Displayed;
CC       Name=1; Synonyms=Alpha, MRAP-alpha;
CC         IsoId=Q8TCY5-1; Sequence=VSP_021020;
CC       Name=2; Synonyms=Beta, MRAP-beta;
CC         IsoId=Q8TCY5-2; Sequence=VSP_003863, VSP_003864;
CC       Name=3; Synonyms=Short;
CC         IsoId=Q8TCY5-3; Sequence=VSP_003862;
CC   -!- TISSUE SPECIFICITY: Expressed in adrenal cortex, testis, breast,
CC       thyroid, lymph node, ovary and fat. Expressed in adipose tissues.
CC       {ECO:0000269|PubMed:15654338}.
CC   -!- DISEASE: Glucocorticoid deficiency 2 (GCCD2) [MIM:607398]: A form of
CC       glucocorticoid deficiency, a rare autosomal recessive disorder
CC       characterized by resistance to ACTH action on the adrenal cortex,
CC       adrenal insufficiency and an inability of the adrenal cortex to produce
CC       cortisol. It usually presents in the neonatal period or in early
CC       childhood with episodes of hypoglycemia and other symptoms related to
CC       cortisol deficiency, including failure to thrive, recurrent illnesses
CC       or infections, convulsions, and shock. In a small number of patients
CC       hypoglycemia can be sufficiently severe and persistent that it leads to
CC       serious long-term neurological damage or death. The diagnosis is
CC       readily confirmed with a low plasma cortisol measurement in the
CC       presence of an elevated ACTH level, and normal aldosterone and plasma
CC       renin measurements. {ECO:0000269|PubMed:15654338}. Note=The disease is
CC       caused by variants affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the MRAP family. {ECO:0000305}.
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DR   EMBL; AF483549; AAL86908.1; -; mRNA.
DR   EMBL; AY079152; AAL80042.1; -; mRNA.
DR   EMBL; AF454915; AAL51048.1; -; mRNA.
DR   EMBL; AF454916; AAL51049.1; -; mRNA.
DR   EMBL; BC062721; AAH62721.1; -; mRNA.
DR   CCDS; CCDS13612.1; -. [Q8TCY5-2]
DR   CCDS; CCDS13613.1; -. [Q8TCY5-4]
DR   RefSeq; NP_001272323.1; NM_001285394.1. [Q8TCY5-3]
DR   RefSeq; NP_848932.1; NM_178817.3. [Q8TCY5-4]
DR   RefSeq; NP_996781.1; NM_206898.1. [Q8TCY5-2]
DR   RefSeq; XP_006724091.1; XM_006724028.3.
DR   RefSeq; XP_016883896.1; XM_017028407.1.
DR   PDB; 8GY7; EM; 3.30 A; P=1-172.
DR   PDBsum; 8GY7; -.
DR   AlphaFoldDB; Q8TCY5; -.
DR   SMR; Q8TCY5; -.
DR   BioGRID; 121114; 4.
DR   DIP; DIP-29948N; -.
DR   IntAct; Q8TCY5; 9.
DR   MINT; Q8TCY5; -.
DR   STRING; 9606.ENSP00000382684; -.
DR   iPTMnet; Q8TCY5; -.
DR   PhosphoSitePlus; Q8TCY5; -.
DR   BioMuta; MRAP; -.
DR   DMDM; 116242634; -.
DR   MassIVE; Q8TCY5; -.
DR   PaxDb; 9606-ENSP00000382684; -.
DR   PeptideAtlas; Q8TCY5; -.
DR   ProteomicsDB; 74194; -. [Q8TCY5-3]
DR   Antibodypedia; 22543; 177 antibodies from 29 providers.
DR   DNASU; 56246; -.
DR   Ensembl; ENST00000303645.10; ENSP00000306697.5; ENSG00000170262.13. [Q8TCY5-4]
DR   Ensembl; ENST00000339944.4; ENSP00000343661.4; ENSG00000170262.13. [Q8TCY5-2]
DR   Ensembl; ENST00000399784.6; ENSP00000382684.2; ENSG00000170262.13. [Q8TCY5-4]
DR   GeneID; 56246; -.
DR   KEGG; hsa:56246; -.
DR   MANE-Select; ENST00000303645.10; ENSP00000306697.5; NM_001379228.1; NP_001366157.1.
DR   UCSC; uc002ypj.4; human. [Q8TCY5-4]
DR   AGR; HGNC:1304; -.
DR   CTD; 56246; -.
DR   DisGeNET; 56246; -.
DR   GeneCards; MRAP; -.
DR   HGNC; HGNC:1304; MRAP.
DR   HPA; ENSG00000170262; Group enriched (adipose tissue, adrenal gland, breast).
DR   MalaCards; MRAP; -.
DR   MIM; 607398; phenotype.
DR   MIM; 609196; gene.
DR   neXtProt; NX_Q8TCY5; -.
DR   OpenTargets; ENSG00000170262; -.
DR   Orphanet; 361; Familial glucocorticoid deficiency.
DR   PharmGKB; PA25856; -.
DR   VEuPathDB; HostDB:ENSG00000170262; -.
DR   eggNOG; ENOG502SB3E; Eukaryota.
DR   GeneTree; ENSGT00650000093475; -.
DR   HOGENOM; CLU_133578_0_0_1; -.
DR   InParanoid; Q8TCY5; -.
DR   OMA; CHREPLG; -.
DR   OrthoDB; 5358677at2759; -.
DR   PhylomeDB; Q8TCY5; -.
DR   TreeFam; TF338691; -.
DR   PathwayCommons; Q8TCY5; -.
DR   SignaLink; Q8TCY5; -.
DR   SIGNOR; Q8TCY5; -.
DR   BioGRID-ORCS; 56246; 10 hits in 1140 CRISPR screens.
DR   ChiTaRS; MRAP; human.
DR   GenomeRNAi; 56246; -.
DR   Pharos; Q8TCY5; Tbio.
DR   PRO; PR:Q8TCY5; -.
DR   Proteomes; UP000005640; Chromosome 21.
DR   RNAct; Q8TCY5; Protein.
DR   Bgee; ENSG00000170262; Expressed in right adrenal gland and 104 other cell types or tissues.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:BHF-UCL.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR   GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL.
DR   GO; GO:0031780; F:corticotropin hormone receptor binding; IPI:BHF-UCL.
DR   GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR   GO; GO:0030545; F:signaling receptor regulator activity; IBA:GO_Central.
DR   GO; GO:0070996; F:type 1 melanocortin receptor binding; IPI:BHF-UCL.
DR   GO; GO:0031781; F:type 3 melanocortin receptor binding; IPI:BHF-UCL.
DR   GO; GO:0031782; F:type 4 melanocortin receptor binding; IPI:BHF-UCL.
DR   GO; GO:0031783; F:type 5 melanocortin receptor binding; IPI:BHF-UCL.
DR   GO; GO:0106072; P:negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; IDA:BHF-UCL.
DR   GO; GO:1903077; P:negative regulation of protein localization to plasma membrane; IDA:BHF-UCL.
DR   GO; GO:0106071; P:positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; IDA:BHF-UCL.
DR   GO; GO:0072659; P:protein localization to plasma membrane; IDA:BHF-UCL.
DR   GO; GO:0106070; P:regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; IBA:GO_Central.
DR   InterPro; IPR028111; MRAP.
DR   PANTHER; PTHR28675:SF2; MELANOCORTIN-2 RECEPTOR ACCESSORY PROTEIN; 1.
DR   PANTHER; PTHR28675; MELANOCORTIN-2 RECEPTOR ACCESSORY PROTEIN 2; 1.
DR   Pfam; PF15183; MRAP; 1.
DR   Genevisible; Q8TCY5; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Cell membrane; Endoplasmic reticulum;
KW   Membrane; Reference proteome; Transmembrane; Transmembrane helix.
FT   CHAIN           1..172
FT                   /note="Melanocortin-2 receptor accessory protein"
FT                   /id="PRO_0000096570"
FT   TRANSMEM        38..58
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   REGION          105..136
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          151..172
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   VAR_SEQ         1..59
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:12036298"
FT                   /id="VSP_003862"
FT   VAR_SEQ         68
FT                   /note="M -> MR (in isoform 1)"
FT                   /evidence="ECO:0000303|PubMed:12054497"
FT                   /id="VSP_021020"
FT   VAR_SEQ         69..101
FT                   /note="RNSPKHHQTCPWSHGLNLHLCIQKCLPCHREPL -> SFNTDESLLHSEVLP
FT                   QTRAISCDELQAPREEGAA (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:12054497"
FT                   /id="VSP_003863"
FT   VAR_SEQ         102..172
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:12054497"
FT                   /id="VSP_003864"
FT   STRAND          18..20
FT                   /evidence="ECO:0007829|PDB:8GY7"
FT   TURN            28..30
FT                   /evidence="ECO:0007829|PDB:8GY7"
FT   HELIX           37..62
FT                   /evidence="ECO:0007829|PDB:8GY7"
SQ   SEQUENCE   172 AA;  19136 MW;  9F93F39B40FAAFEA CRC64;
     MANGTNASAP YYSYEYYLDY LDLIPVDEKK LKAHKHSIVI AFWVSLAAFV VLLFLILLYM
     SWSASPQMRN SPKHHQTCPW SHGLNLHLCI QKCLPCHREP LATSQAQASS VEPGSRTGPD
     QPLRQESSST LPLGGFQTHP TLLWELTLNG GPLVRSKPSE PPPGDRTSQL QS
//