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MRAP2_HUMAN
ID   MRAP2_HUMAN             Reviewed;         205 AA.
AC   Q96G30; A8K9M1; Q8IXM9; Q8N2D1;
DT   05-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2004, sequence version 2.
DT   03-AUG-2022, entry version 141.
DE   RecName: Full=Melanocortin-2 receptor accessory protein 2;
DE            Short=MC2R accessory protein 2;
GN   Name=MRAP2; Synonyms=C6orf117;
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 MRNA].
RC   TISSUE=Amygdala, and Kidney;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=14574404; DOI=10.1038/nature02055;
RA   Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA   Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA   Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA   Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA   Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA   Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA   Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA   Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA   Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA   French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA   Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA   Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA   Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA   Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA   Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA   Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA   Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA   Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA   Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA   Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA   Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA   Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA   Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA   Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA   Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA   West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA   Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA   Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA   Rogers J., Beck S.;
RT   "The DNA sequence and analysis of human chromosome 6.";
RL   Nature 425:805-811(2003).
RN   [3]
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   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain, and Colon;
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   [5]
RP   FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, GLYCOSYLATION AT ASN-9,
RP   INTERACTION WITH MC1R; MC2R; MC3R; MC4R; MC5R AND MRAP, TISSUE SPECIFICITY,
RP   AND MUTAGENESIS OF ASN-9.
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   [6]
RP   FUNCTION, SUBUNIT, TOPOLOGY, AND INTERACTION WITH MRAP.
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   [7]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-89, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Erythroleukemia;
RX   PubMed=23186163; DOI=10.1021/pr300630k;
RA   Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA   Mohammed S.;
RT   "Toward a comprehensive characterization of a human cancer cell
RT   phosphoproteome.";
RL   J. Proteome Res. 12:260-271(2013).
RN   [8]
RP   POLYMORPHISM, INVOLVEMENT IN OBESITY, AND VARIANTS TYR-88; VAL-115 AND
RP   CYS-125.
RX   PubMed=23869016; DOI=10.1126/science.1233000;
RA   Asai M., Ramachandrappa S., Joachim M., Shen Y., Zhang R., Nuthalapati N.,
RA   Ramanathan V., Strochlic D.E., Ferket P., Linhart K., Ho C.,
RA   Novoselova T.V., Garg S., Ridderstrale M., Marcus C., Hirschhorn J.N.,
RA   Keogh J.M., O'Rahilly S., Chan L.F., Clark A.J., Farooqi I.S.,
RA   Majzoub J.A.;
RT   "Loss of function of the melanocortin 2 receptor accessory protein 2 is
RT   associated with mammalian obesity.";
RL   Science 341:275-278(2013).
CC   -!- FUNCTION: Modulator of melanocortin receptor 4 (MC4R), a receptor
CC       involved in energy homeostasis. Plays a central role in the control of
CC       energy homeostasis and body weight regulation by increasing ligand-
CC       sensitivity of MC4R and MC4R-mediated generation of cAMP (By
CC       similarity). May also act as a negative regulator of MC2R: competes
CC       with MRAP for binding to MC2R and impairs the binding of corticotropin
CC       (ACTH) to MC2R. May also regulate activity of other melanocortin
CC       receptors (MC1R, MC3R and MC5R); however, additional evidence is
CC       required in vivo. {ECO:0000250, ECO:0000269|PubMed:19329486,
CC       ECO:0000269|PubMed:20371771}.
CC   -!- SUBUNIT: Homodimer and heterodimer. Forms antiparallel homodimers and
CC       heterodimers with MRAP. Interacts with MC1R, MC2R, MC3R, MC4R and MC5R.
CC       {ECO:0000269|PubMed:19329486, ECO:0000269|PubMed:20371771}.
CC   -!- INTERACTION:
CC       Q96G30; Q96BI3: APH1A; NbExp=3; IntAct=EBI-9537218, EBI-2606935;
CC       Q96G30; P23560-2: BDNF; NbExp=3; IntAct=EBI-9537218, EBI-12275524;
CC       Q96G30; Q6UXK2: ISLR2; NbExp=3; IntAct=EBI-9537218, EBI-1266923;
CC       Q96G30; Q01718: MC2R; NbExp=2; IntAct=EBI-9537218, EBI-9537171;
CC       Q96G30; Q8TCY5: MRAP; NbExp=3; IntAct=EBI-9537218, EBI-9538727;
CC       Q96G30; Q96G30: MRAP2; NbExp=3; IntAct=EBI-9537218, EBI-9537218;
CC       Q96G30; O43765: SGTA; NbExp=6; IntAct=EBI-9537218, EBI-347996;
CC       Q96G30; Q96HE8: TMEM80; NbExp=3; IntAct=EBI-9537218, EBI-11742770;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:19329486};
CC       Single-pass membrane protein {ECO:0000269|PubMed:19329486}. Endoplasmic
CC       reticulum membrane {ECO:0000269|PubMed:19329486}; Single-pass membrane
CC       protein {ECO:0000269|PubMed:19329486}. 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. {ECO:0000269|PubMed:20371771}.
CC   -!- TISSUE SPECIFICITY: Expressed in the adrenal gland and brain. Not
CC       expressed in other tissues. {ECO:0000269|PubMed:19329486}.
CC   -!- POLYMORPHISM: Genetic variations in MRAP2 define the body mass index
CC       quantitative trait locus 18 (BMIQ18) [MIM:615457]. Variance in body
CC       mass index is a susceptibility factor for obesity.
CC       {ECO:0000269|PubMed:23869016}.
CC   -!- DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by
CC       an increase of body weight beyond the limitation of skeletal and
CC       physical requirements, as the result of excessive accumulation of body
CC       fat. {ECO:0000269|PubMed:23869016}. Note=Disease susceptibility may be
CC       associated with variants affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the MRAP family. {ECO:0000305}.
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DR   EMBL; AK090775; BAC03517.1; -; mRNA.
DR   EMBL; AK292736; BAF85425.1; -; mRNA.
DR   EMBL; AL161621; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471051; EAW48646.1; -; Genomic_DNA.
DR   EMBL; BC010003; AAH10003.2; -; mRNA.
DR   EMBL; BC039855; AAH39855.1; -; mRNA.
DR   CCDS; CCDS5001.1; -.
DR   RefSeq; NP_001333470.1; NM_001346541.1.
DR   RefSeq; NP_001333471.1; NM_001346542.1.
DR   RefSeq; NP_001333473.1; NM_001346544.1.
DR   RefSeq; NP_612418.2; NM_138409.3.
DR   RefSeq; XP_016865709.1; XM_017010220.1.
DR   AlphaFoldDB; Q96G30; -.
DR   BioGRID; 125195; 77.
DR   DIP; DIP-48793N; -.
DR   IntAct; Q96G30; 65.
DR   MINT; Q96G30; -.
DR   STRING; 9606.ENSP00000257776; -.
DR   GlyGen; Q96G30; 1 site.
DR   iPTMnet; Q96G30; -.
DR   PhosphoSitePlus; Q96G30; -.
DR   BioMuta; MRAP2; -.
DR   DMDM; 68565259; -.
DR   PaxDb; Q96G30; -.
DR   PeptideAtlas; Q96G30; -.
DR   PRIDE; Q96G30; -.
DR   ProteomicsDB; 76591; -.
DR   Antibodypedia; 2456; 116 antibodies from 20 providers.
DR   DNASU; 112609; -.
DR   Ensembl; ENST00000257776.5; ENSP00000257776.4; ENSG00000135324.6.
DR   GeneID; 112609; -.
DR   KEGG; hsa:112609; -.
DR   MANE-Select; ENST00000257776.5; ENSP00000257776.4; NM_138409.4; NP_612418.2.
DR   UCSC; uc003pkg.5; human.
DR   CTD; 112609; -.
DR   DisGeNET; 112609; -.
DR   GeneCards; MRAP2; -.
DR   HGNC; HGNC:21232; MRAP2.
DR   HPA; ENSG00000135324; Tissue enhanced (brain).
DR   MalaCards; MRAP2; -.
DR   MIM; 601665; phenotype.
DR   MIM; 615410; gene.
DR   MIM; 615457; phenotype.
DR   neXtProt; NX_Q96G30; -.
DR   OpenTargets; ENSG00000135324; -.
DR   PharmGKB; PA162396161; -.
DR   VEuPathDB; HostDB:ENSG00000135324; -.
DR   eggNOG; ENOG502RYQM; Eukaryota.
DR   GeneTree; ENSGT00650000093438; -.
DR   HOGENOM; CLU_110753_0_0_1; -.
DR   InParanoid; Q96G30; -.
DR   OMA; WDYEYYE; -.
DR   OrthoDB; 1318662at2759; -.
DR   PhylomeDB; Q96G30; -.
DR   TreeFam; TF338691; -.
DR   PathwayCommons; Q96G30; -.
DR   SignaLink; Q96G30; -.
DR   SIGNOR; Q96G30; -.
DR   BioGRID-ORCS; 112609; 14 hits in 1076 CRISPR screens.
DR   GenomeRNAi; 112609; -.
DR   Pharos; Q96G30; Tbio.
DR   PRO; PR:Q96G30; -.
DR   Proteomes; UP000005640; Chromosome 6.
DR   RNAct; Q96G30; protein.
DR   Bgee; ENSG00000135324; Expressed in lateral nuclear group of thalamus and 141 other tissues.
DR   Genevisible; Q96G30; HS.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:BHF-UCL.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:0097009; P:energy homeostasis; ISS:UniProtKB.
DR   GO; GO:0006112; P:energy reserve metabolic process; ISS:UniProtKB.
DR   GO; GO:0007631; P:feeding behavior; ISS:UniProtKB.
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; PTHR28675; 1.
DR   Pfam; PF15183; MRAP; 1.
PE   1: Evidence at protein level;
KW   Cell membrane; Endoplasmic reticulum; Glycoprotein; Membrane; Obesity;
KW   Phosphoprotein; Reference proteome; Transmembrane; Transmembrane helix.
FT   CHAIN           1..205
FT                   /note="Melanocortin-2 receptor accessory protein 2"
FT                   /id="PRO_0000089522"
FT   TRANSMEM        45..65
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   MOD_RES         89
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   CARBOHYD        9
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:19329486"
FT   VARIANT         88
FT                   /note="N -> Y (found in a patient with obesity; unknown
FT                   pathological significance; dbSNP:rs761868293)"
FT                   /evidence="ECO:0000269|PubMed:23869016"
FT                   /id="VAR_069986"
FT   VARIANT         115
FT                   /note="L -> V (found in a patient with obesity; unknown
FT                   pathological significance; dbSNP:rs368589399)"
FT                   /evidence="ECO:0000269|PubMed:23869016"
FT                   /id="VAR_069987"
FT   VARIANT         125
FT                   /note="R -> C (found in a patient with obesity; unknown
FT                   pathological significance; dbSNP:rs148904867)"
FT                   /evidence="ECO:0000269|PubMed:23869016"
FT                   /id="VAR_069988"
FT   MUTAGEN         9
FT                   /note="N->Q: Abolishes N-glycosylation."
FT                   /evidence="ECO:0000269|PubMed:19329486"
FT   CONFLICT        62
FT                   /note="F -> I (in Ref. 1; BAC03517)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   205 AA;  23548 MW;  3B18B493AE75260B CRC64;
     MSAQRLISNR TSQQSASNSD YTWEYEYYEI GPVSFEGLKA HKYSIVIGFW VGLAVFVIFM
     FFVLTLLTKT GAPHQDNAES SEKRFRMNSF VSDFGRPLEP DKVFSRQGNE ESRSLFHCYI
     NEVERLDRAK ACHQTTALDS DVQLQEAIRS SGQPEEELNR LMKFDIPNFV NTDQNYFGED
     DLLISEPPIV LETKPLSQTS HKDLD
 
 
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