ID   RGMA_HUMAN              Reviewed;         450 AA.
AC   Q96B86; B2RTW1; B7Z5S8; F5GXQ7; F5GZU6; G3V518; Q0JV97; Q8NC80; Q9H0E6;
AC   Q9NPM3;
DT   16-AUG-2004, integrated into UniProtKB/Swiss-Prot.
DT   23-FEB-2022, sequence version 4.
DT   24-JAN-2024, entry version 155.
DE   RecName: Full=Repulsive guidance molecule A {ECO:0000305};
DE   AltName: Full=RGM domain family member A;
DE   Flags: Precursor;
GN   Name=RGMA {ECO:0000312|HGNC:HGNC:30308}; Synonyms=RGM;
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] (ISOFORM 2).
RC   TISSUE=Retina;
RG   The European IMAGE consortium;
RL   Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Testis;
RX   PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA   Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA   Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA   Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA   Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA   Klein M., Poustka A.;
RT   "Towards a catalog of human genes and proteins: sequencing and analysis of
RT   500 novel complete protein coding human cDNAs.";
RL   Genome Res. 11:422-435(2001).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC   TISSUE=Teratocarcinoma;
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   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16572171; DOI=10.1038/nature04601;
RA   Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA   Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA   FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA   Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA   Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA   DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA   Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA   Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA   Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA   O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA   Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA   Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT   "Analysis of the DNA sequence and duplication history of human chromosome
RT   15.";
RL   Nature 440:671-675(2006).
RN   [5]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC   TISSUE=Brain, and Uterus;
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   [7]
RP   FUNCTION.
RX   PubMed=19273616; DOI=10.1083/jcb.200807029;
RA   Hata K., Kaibuchi K., Inagaki S., Yamashita T.;
RT   "Unc5B associates with LARG to mediate the action of repulsive guidance
RT   molecule.";
RL   J. Cell Biol. 184:737-750(2009).
RN   [8]
RP   FUNCTION.
RX   PubMed=19458235; DOI=10.1523/jneurosci.0927-09.2009;
RA   Endo M., Yamashita T.;
RT   "Inactivation of Ras by p120GAP via focal adhesion kinase dephosphorylation
RT   mediates RGMa-induced growth cone collapse.";
RL   J. Neurosci. 29:6649-6662(2009).
CC   -!- FUNCTION: Member of the repulsive guidance molecule (RGM) family that
CC       performs several functions in the developing and adult nervous system.
CC       Regulates cephalic neural tube closure, inhibits neurite outgrowth and
CC       cortical neuron branching, and the formation of mature synapses.
CC       Binding to its receptor NEO1/neogenin induces activation of RHOA-
CC       ROCK1/Rho-kinase signaling pathway through UNC5B-ARHGEF12/LARG-
CC       PTK2/FAK1 cascade, leading to collapse of the neuronal growth cone and
CC       neurite outgrowth inhibition. Furthermore, RGMA binding to
CC       NEO1/neogenin leads to HRAS inactivation by influencing HRAS-PTK2/FAK1-
CC       AKT1 pathway. It also functions as a bone morphogenetic protein (BMP)
CC       coreceptor that may signal through SMAD1, SMAD5, and SMAD8.
CC       {ECO:0000269|PubMed:19273616, ECO:0000269|PubMed:19458235}.
CC   -!- SUBUNIT: Interacts with NEO1, BMP2 and BMP4. {ECO:0000250}.
CC   -!- INTERACTION:
CC       Q96B86; Q9NYB0: TERF2IP; NbExp=2; IntAct=EBI-722102, EBI-750109;
CC       Q96B86-1; P12643: BMP2; NbExp=2; IntAct=EBI-16155394, EBI-1029262;
CC       Q96B86-3; Q05BL1: TP53BP2; NbExp=3; IntAct=EBI-14497860, EBI-11952721;
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Lipid-anchor, GPI-
CC       anchor {ECO:0000250}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=Q96B86-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q96B86-3; Sequence=VSP_054070;
CC       Name=3;
CC         IsoId=Q96B86-4; Sequence=VSP_054071;
CC   -!- PTM: Autocatalytically cleaved at low pH; the two chains remain linked
CC       via two disulfide bonds. {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the repulsive guidance molecule (RGM) family.
CC       {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH15886.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC       Sequence=CAB98207.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; AL390083; CAB98207.1; ALT_INIT; mRNA.
DR   EMBL; AL136826; CAB66760.1; -; mRNA.
DR   EMBL; AK074910; BAC11285.1; -; mRNA.
DR   EMBL; AK074966; BAC11321.1; -; mRNA.
DR   EMBL; AK074980; BAC11330.1; -; mRNA.
DR   EMBL; AK299363; BAH13014.1; -; mRNA.
DR   EMBL; AC087641; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471101; EAX02167.1; -; Genomic_DNA.
DR   EMBL; BC015886; AAH15886.2; ALT_INIT; mRNA.
DR   EMBL; BC140838; AAI40839.1; -; mRNA.
DR   EMBL; BC151132; AAI51133.1; -; mRNA.
DR   CCDS; CCDS45357.1; -. [Q96B86-1]
DR   CCDS; CCDS53973.1; -. [Q96B86-3]
DR   CCDS; CCDS53974.1; -. [Q96B86-4]
DR   RefSeq; NP_001159755.1; NM_001166283.1. [Q96B86-4]
DR   RefSeq; NP_001159758.1; NM_001166286.1. [Q96B86-3]
DR   RefSeq; NP_001159759.1; NM_001166287.1. [Q96B86-3]
DR   RefSeq; NP_001159760.1; NM_001166288.1. [Q96B86-3]
DR   RefSeq; NP_001159761.1; NM_001166289.1. [Q96B86-3]
DR   RefSeq; NP_064596.2; NM_020211.2. [Q96B86-1]
DR   PDB; 4UHY; X-ray; 3.20 A; C=46-139.
DR   PDB; 6Z3G; X-ray; 2.78 A; B=54-139.
DR   PDBsum; 4UHY; -.
DR   PDBsum; 6Z3G; -.
DR   AlphaFoldDB; Q96B86; -.
DR   SMR; Q96B86; -.
DR   BioGRID; 121284; 17.
DR   DIP; DIP-61606N; -.
DR   IntAct; Q96B86; 16.
DR   STRING; 9606.ENSP00000452126; -.
DR   ChEMBL; CHEMBL4630886; -.
DR   GlyCosmos; Q96B86; 4 sites, 1 glycan.
DR   GlyGen; Q96B86; 4 sites, 1 O-linked glycan (1 site).
DR   iPTMnet; Q96B86; -.
DR   PhosphoSitePlus; Q96B86; -.
DR   BioMuta; RGMA; -.
DR   DMDM; 296452979; -.
DR   EPD; Q96B86; -.
DR   MassIVE; Q96B86; -.
DR   PaxDb; 9606-ENSP00000452126; -.
DR   PeptideAtlas; Q96B86; -.
DR   ProteomicsDB; 25133; -.
DR   ProteomicsDB; 33395; -.
DR   ProteomicsDB; 76054; -. [Q96B86-1]
DR   ABCD; Q96B86; 1 sequenced antibody.
DR   Antibodypedia; 43886; 313 antibodies from 27 providers.
DR   DNASU; 56963; -.
DR   Ensembl; ENST00000329082.12; ENSP00000330005.7; ENSG00000182175.15. [Q96B86-1]
DR   Ensembl; ENST00000425933.6; ENSP00000404442.2; ENSG00000182175.15. [Q96B86-3]
DR   Ensembl; ENST00000542321.6; ENSP00000440025.2; ENSG00000182175.15. [Q96B86-3]
DR   Ensembl; ENST00000543599.5; ENSP00000442498.1; ENSG00000182175.15. [Q96B86-3]
DR   Ensembl; ENST00000557301.2; ENSP00000452126.1; ENSG00000182175.15. [Q96B86-4]
DR   GeneID; 56963; -.
DR   KEGG; hsa:56963; -.
DR   MANE-Select; ENST00000329082.12; ENSP00000330005.7; NM_020211.3; NP_064596.2.
DR   UCSC; uc002bsq.3; human. [Q96B86-1]
DR   AGR; HGNC:30308; -.
DR   CTD; 56963; -.
DR   DisGeNET; 56963; -.
DR   GeneCards; RGMA; -.
DR   HGNC; HGNC:30308; RGMA.
DR   HPA; ENSG00000182175; Tissue enhanced (skeletal).
DR   MIM; 607362; gene.
DR   neXtProt; NX_Q96B86; -.
DR   OpenTargets; ENSG00000182175; -.
DR   PharmGKB; PA128394693; -.
DR   VEuPathDB; HostDB:ENSG00000182175; -.
DR   eggNOG; ENOG502QSTJ; Eukaryota.
DR   GeneTree; ENSGT00950000183112; -.
DR   HOGENOM; CLU_032775_1_1_1; -.
DR   InParanoid; Q96B86; -.
DR   OMA; LCWLCLL; -.
DR   OrthoDB; 4091162at2759; -.
DR   PhylomeDB; Q96B86; -.
DR   TreeFam; TF329836; -.
DR   PathwayCommons; Q96B86; -.
DR   Reactome; R-HSA-373752; Netrin-1 signaling.
DR   SignaLink; Q96B86; -.
DR   SIGNOR; Q96B86; -.
DR   BioGRID-ORCS; 56963; 16 hits in 1142 CRISPR screens.
DR   ChiTaRS; RGMA; human.
DR   GeneWiki; RGMA; -.
DR   GenomeRNAi; 56963; -.
DR   Pharos; Q96B86; Tbio.
DR   PRO; PR:Q96B86; -.
DR   Proteomes; UP000005640; Chromosome 15.
DR   RNAct; Q96B86; Protein.
DR   Bgee; ENSG00000182175; Expressed in lower esophagus muscularis layer and 163 other cell types or tissues.
DR   ExpressionAtlas; Q96B86; baseline and differential.
DR   GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:LIFEdb.
DR   GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR   GO; GO:0098552; C:side of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0015026; F:coreceptor activity; IBA:GO_Central.
DR   GO; GO:1990459; F:transferrin receptor binding; IPI:BHF-UCL.
DR   GO; GO:0030509; P:BMP signaling pathway; IBA:GO_Central.
DR   GO; GO:0006509; P:membrane protein ectodomain proteolysis; IEA:Ensembl.
DR   GO; GO:0048681; P:negative regulation of axon regeneration; IEA:Ensembl.
DR   GO; GO:0048671; P:negative regulation of collateral sprouting; IEA:Ensembl.
DR   GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
DR   GO; GO:0031175; P:neuron projection development; IEA:Ensembl.
DR   GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IEA:Ensembl.
DR   GO; GO:0010976; P:positive regulation of neuron projection development; IEA:Ensembl.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR   GO; GO:0030510; P:regulation of BMP signaling pathway; IEA:Ensembl.
DR   Gene3D; 3.40.1000.10; Mog1/PsbP, alpha/beta/alpha sandwich; 1.
DR   InterPro; IPR040287; RGM.
DR   InterPro; IPR009496; RGM_C.
DR   InterPro; IPR010536; RGM_N.
DR   PANTHER; PTHR31428:SF4; REPULSIVE GUIDANCE MOLECULE A; 1.
DR   PANTHER; PTHR31428; RGM DOMAIN FAMILY MEMBER DRAG-1; 1.
DR   Pfam; PF06534; RGM_C; 1.
DR   Pfam; PF06535; RGM_N; 1.
DR   Genevisible; Q96B86; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Autocatalytic cleavage; Cell membrane;
KW   Disulfide bond; Glycoprotein; GPI-anchor; Lipoprotein; Membrane;
KW   Reference proteome; Signal.
FT   SIGNAL          1..47
FT                   /evidence="ECO:0000255"
FT   PROPEP          48..168
FT                   /note="Removed in mature form"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000030385"
FT   CHAIN           169..424
FT                   /note="Repulsive guidance molecule A"
FT                   /id="PRO_0000030386"
FT   PROPEP          425..450
FT                   /note="Removed in mature form"
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000030387"
FT   REGION          113..140
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            168..169
FT                   /note="Cleavage; by autolysis"
FT                   /evidence="ECO:0000250"
FT   LIPID           424
FT                   /note="GPI-anchor amidated alanine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        114
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        159
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        389
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        145..226
FT                   /evidence="ECO:0000250"
FT   DISULFID        163..315
FT                   /evidence="ECO:0000250"
FT   VAR_SEQ         1..16
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039,
FT                   ECO:0000303|PubMed:15489334, ECO:0000303|Ref.1"
FT                   /id="VSP_054070"
FT   VAR_SEQ         1..4
FT                   /note="MQPP -> MGGLGPRRAGTS (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_054071"
FT   VARIANT         415
FT                   /note="E -> D (in dbSNP:rs4238485)"
FT                   /id="VAR_062144"
FT   VARIANT         431
FT                   /note="A -> V (in dbSNP:rs4778078)"
FT                   /id="VAR_060105"
FT   CONFLICT        199
FT                   /note="V -> A (in Ref. 3; BAC11285)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        314
FT                   /note="L -> P (in Ref. 3; BAH13014)"
FT                   /evidence="ECO:0000305"
FT   TURN            57..59
FT                   /evidence="ECO:0007829|PDB:6Z3G"
FT   HELIX           79..87
FT                   /evidence="ECO:0007829|PDB:6Z3G"
FT   TURN            88..93
FT                   /evidence="ECO:0007829|PDB:6Z3G"
FT   HELIX           97..110
FT                   /evidence="ECO:0007829|PDB:6Z3G"
FT   TURN            111..114
FT                   /evidence="ECO:0007829|PDB:6Z3G"
SQ   SEQUENCE   450 AA;  49361 MW;  E3244FA591182DCF CRC64;
     MQPPRERLVV TGRAGWMGMG RGAGRSALGF WPTLAFLLCS FPAATSPCKI LKCNSEFWSA
     TSGSHAPASD DTPEFCAALR SYALCTRRTA RTCRGDLAYH SAVHGIEDLM SQHNCSKDGP
     TSQPRLRTLP PAGDSQERSD SPEICHYEKS FHKHSATPNY THCGLFGDPH LRTFTDRFQT
     CKVQGAWPLI DNNYLNVQVT NTPVLPGSAA TATSKLTIIF KNFQECVDQK VYQAEMDELP
     AAFVDGSKNG GDKHGANSLK ITEKVSGQHV EIQAKYIGTT IVVRQVGRYL TFAVRMPEEV
     VNAVEDWDSQ GLYLCLRGCP LNQQIDFQAF HTNAEGTGAR RLAAASPAPT APETFPYETA
     VAKCKEKLPV EDLYYQACVF DLLTTGDVNF TLAAYYALED VKMLHSNKDK LHLYERTRDL
     PGRAAAGLPL APRPLLGALV PLLALLPVFC
//