GFRAL_MOUSE
ID GFRAL_MOUSE Reviewed; 393 AA.
AC Q6SJE0; Q6SJD9;
DT 13-JUN-2006, integrated into UniProtKB/Swiss-Prot.
DT 16-AUG-2004, sequence version 2.
DT 03-AUG-2022, entry version 104.
DE RecName: Full=GDNF family receptor alpha-like;
DE Flags: Precursor;
GN Name=Gfral; Synonyms=Gral;
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] (ISOFORMS A AND B).
RC STRAIN=C57BL/6J;
RA Li Z., Wang B., Zhou J.;
RT "Molecular cloning and characterization of GRAL, a novel GDNF receptor
RT alpha-like gene.";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP DISRUPTION PHENOTYPE, FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=28953886; DOI=10.1038/nature24042;
RA Hsu J.Y., Crawley S., Chen M., Ayupova D.A., Lindhout D.A., Higbee J.,
RA Kutach A., Joo W., Gao Z., Fu D., To C., Mondal K., Li B., Kekatpure A.,
RA Wang M., Laird T., Horner G., Chan J., McEntee M., Lopez M.,
RA Lakshminarasimhan D., White A., Wang S.P., Yao J., Yie J., Matern H.,
RA Solloway M., Haldankar R., Parsons T., Tang J., Shen W.D., Alice Chen Y.,
RA Tian H., Allan B.B.;
RT "Non-homeostatic body weight regulation through a brainstem-restricted
RT receptor for GDF15.";
RL Nature 550:255-259(2017).
RN [3]
RP ERRATUM OF PUBMED:28953886.
RX PubMed=29144449; DOI=10.1038/nature24481;
RA Hsu J.Y., Crawley S., Chen M., Ayupova D.A., Lindhout D.A., Higbee J.,
RA Kutach A., Joo W., Gao Z., Fu D., To C., Mondal K., Li B., Kekatpure A.,
RA Wang M., Laird T., Horner G., Chan J., McEntee M., Lopez M.,
RA Lakshminarasimhan D., White A., Wang S.P., Yao J., Yie J., Matern H.,
RA Solloway M., Haldankar R., Parsons T., Tang J., Shen W.D., Alice Chen Y.,
RA Tian H., Allan B.B.;
RT "Non-homeostatic body weight regulation through a brainstem-restricted
RT receptor for GDF15.";
RL Nature 551:398-398(2017).
RN [4]
RP DISRUPTION PHENOTYPE, FUNCTION, AND INTERACTION WITH GDF15.
RX PubMed=28846098; DOI=10.1038/nm.4393;
RA Emmerson P.J., Wang F., Du Y., Liu Q., Pickard R.T., Gonciarz M.D.,
RA Coskun T., Hamang M.J., Sindelar D.K., Ballman K.K., Foltz L.A.,
RA Muppidi A., Alsina-Fernandez J., Barnard G.C., Tang J.X., Liu X., Mao X.,
RA Siegel R., Sloan J.H., Mitchell P.J., Zhang B.B., Gimeno R.E., Shan B.,
RA Wu X.;
RT "The metabolic effects of GDF15 are mediated by the orphan receptor
RT GFRAL.";
RL Nat. Med. 23:1215-1219(2017).
RN [5]
RP FUNCTION, INTERACTION WITH GDF15 AND RET, TISSUE SPECIFICITY, AND
RP DISRUPTION PHENOTYPE.
RX PubMed=28846099; DOI=10.1038/nm.4394;
RA Yang L., Chang C.C., Sun Z., Madsen D., Zhu H., Padkjaer S.B., Wu X.,
RA Huang T., Hultman K., Paulsen S.J., Wang J., Bugge A., Frantzen J.B.,
RA Noergaard P., Jeppesen J.F., Yang Z., Secher A., Chen H., Li X., John L.M.,
RA Shan B., He Z., Gao X., Su J., Hansen K.T., Yang W., Joergensen S.B.;
RT "GFRAL is the receptor for GDF15 and is required for the anti-obesity
RT effects of the ligand.";
RL Nat. Med. 23:1158-1166(2017).
RN [6]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=28846097; DOI=10.1038/nm.4392;
RA Mullican S.E., Lin-Schmidt X., Chin C.N., Chavez J.A., Furman J.L.,
RA Armstrong A.A., Beck S.C., South V.J., Dinh T.Q., Cash-Mason T.D.,
RA Cavanaugh C.R., Nelson S., Huang C., Hunter M.J., Rangwala S.M.;
RT "GFRAL is the receptor for GDF15 and the ligand promotes weight loss in
RT mice and nonhuman primates.";
RL Nat. Med. 23:1150-1157(2017).
CC -!- FUNCTION: Brainstem-restricted receptor for GDF15 which regulates food
CC intake, energy expenditure and body weight in response to metabolic and
CC toxin-induced stresses (PubMed:28953886, PubMed:28846099,
CC PubMed:28846097, PubMed:28846098). Upon interaction with its ligand,
CC GDF15, interacts with RET and induces cellular signaling through
CC activation of MAPK- and AKT- signaling pathways (PubMed:28846098,
CC PubMed:28846099). {ECO:0000269|PubMed:28846097,
CC ECO:0000269|PubMed:28846098, ECO:0000269|PubMed:28846099,
CC ECO:0000269|PubMed:28953886}.
CC -!- SUBUNIT: Interacts (via the extracellular domain) with GDF15 and RET;
CC receptor of GDF15, mediates cellular signaling through interaction with
CC RET after GDF15-binding (PubMed:28846098, PubMed:28846099). Interaction
CC with RET requires previous GDF15-binding (PubMed:28846099).
CC {ECO:0000269|PubMed:28846098, ECO:0000269|PubMed:28846099}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}; Single-pass membrane
CC protein {ECO:0000305}; Extracellular side {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=A;
CC IsoId=Q6SJE0-1; Sequence=Displayed;
CC Name=B;
CC IsoId=Q6SJE0-2; Sequence=VSP_019295, VSP_019296;
CC -!- TISSUE SPECIFICITY: Expressed in the brainstem, restricted to cells in
CC the area postrema and the immediately adjacent region of the nucleus
CC tractus solitarius. {ECO:0000269|PubMed:28846097,
CC ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886}.
CC -!- DISRUPTION PHENOTYPE: On a chow diet, mutants show no difference in
CC food intake, energy expenditure or body weight compare to wild-type
CC controls. On high-fat diet, they gain substantially more weight and are
CC more glucose intolerant. Diet-induced obese mutants are hyperphagic and
CC have 32% greater total mass and 9% greater lean mass than diet-induced
CC obese wild-type mice (PubMed:28953886, PubMed:28846097,
CC PubMed:28846099). Upon chronical administration of GDF15, mutants are
CC refractory to the GDF15 effects in comparison to wild-types that show
CC attenuated food-intake and sustained weightloss (PubMed:28846098,
CC PubMed:28953886, PubMed:28846097, PubMed:28846099).
CC {ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846098,
CC ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886}.
CC -!- SIMILARITY: Belongs to the GDNFR family. {ECO:0000305}.
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DR EMBL; AY457637; AAS13632.2; -; mRNA.
DR EMBL; AY457638; AAS13633.1; -; mRNA.
DR CCDS; CCDS40694.1; -. [Q6SJE0-1]
DR RefSeq; NP_995316.2; NM_205844.3. [Q6SJE0-1]
DR AlphaFoldDB; Q6SJE0; -.
DR SMR; Q6SJE0; -.
DR STRING; 10090.ENSMUSP00000074421; -.
DR GlyGen; Q6SJE0; 4 sites.
DR PaxDb; Q6SJE0; -.
DR PRIDE; Q6SJE0; -.
DR Antibodypedia; 54700; 146 antibodies from 20 providers.
DR DNASU; 404194; -.
DR Ensembl; ENSMUST00000074880; ENSMUSP00000074421; ENSMUSG00000059383. [Q6SJE0-1]
DR Ensembl; ENSMUST00000184693; ENSMUSP00000139120; ENSMUSG00000059383. [Q6SJE0-2]
DR GeneID; 404194; -.
DR KEGG; mmu:404194; -.
DR UCSC; uc009qsy.1; mouse. [Q6SJE0-1]
DR CTD; 389400; -.
DR MGI; MGI:3607786; Gfral.
DR VEuPathDB; HostDB:ENSMUSG00000059383; -.
DR eggNOG; ENOG502RCJT; Eukaryota.
DR GeneTree; ENSGT00730000111274; -.
DR HOGENOM; CLU_058745_0_0_1; -.
DR InParanoid; Q6SJE0; -.
DR OMA; CLNVIHS; -.
DR OrthoDB; 1089046at2759; -.
DR PhylomeDB; Q6SJE0; -.
DR TreeFam; TF331647; -.
DR BioGRID-ORCS; 404194; 2 hits in 72 CRISPR screens.
DR PRO; PR:Q6SJE0; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; Q6SJE0; protein.
DR GO; GO:0015629; C:actin cytoskeleton; ISO:MGI.
DR GO; GO:0009897; C:external side of plasma membrane; ISS:UniProtKB.
DR GO; GO:0005925; C:focal adhesion; ISO:MGI.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR GO; GO:0016167; F:glial cell-derived neurotrophic factor receptor activity; IDA:UniProtKB.
DR GO; GO:0030971; F:receptor tyrosine kinase binding; IPI:UniProtKB.
DR GO; GO:0038023; F:signaling receptor activity; IBA:GO_Central.
DR GO; GO:0035860; P:glial cell-derived neurotrophic factor receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IDA:MGI.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IDA:MGI.
DR GO; GO:0007399; P:nervous system development; IBA:GO_Central.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IMP:GO_Central.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; ISS:UniProtKB.
DR GO; GO:0002023; P:reduction of food intake in response to dietary excess; IDA:UniProtKB.
DR GO; GO:0031098; P:stress-activated protein kinase signaling cascade; IDA:MGI.
DR InterPro; IPR016017; GDNF/GAS1.
DR InterPro; IPR037193; GDNF_alpha.
DR InterPro; IPR003438; GDNF_rcpt.
DR PANTHER; PTHR10269; PTHR10269; 1.
DR Pfam; PF02351; GDNF; 2.
DR SMART; SM00907; GDNF; 3.
DR SUPFAM; SSF110035; SSF110035; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Disulfide bond; Glycoprotein;
KW Membrane; Receptor; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT CHAIN 20..393
FT /note="GDNF family receptor alpha-like"
FT /id="PRO_0000240125"
FT TOPO_DOM 20..349
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 350..370
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 371..393
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 149..228
FT /note="Required for interaction with GDF15"
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT CARBOHYD 59
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 65
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 101
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 115
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 131..189
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT DISULFID 138..144
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT DISULFID 155..167
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT DISULFID 162..210
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT DISULFID 191..198
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT DISULFID 220..291
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT DISULFID 227..233
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT DISULFID 244..275
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT DISULFID 252..258
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT DISULFID 269..316
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT DISULFID 293..304
FT /evidence="ECO:0000250|UniProtKB:Q6UXV0"
FT VAR_SEQ 235..238
FT /note="THYR -> LPNS (in isoform B)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_019295"
FT VAR_SEQ 239..393
FT /note="Missing (in isoform B)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_019296"
FT CONFLICT 20
FT /note="Q -> P (in Ref. 1; AAS13633)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 393 AA; 43964 MW; E3585E89712694B8 CRC64;
MLVFIFLAVT LSSENESSSQ TNDCAHLIQK CLIDANGCEQ SWRSMEDTCL TPGDSCKINN
SLHCNLSIQA LVEKNFQFKE CLCMDDLHCT VNKLFGKKCT NKTDNMEKDN KDKWNLTTTP
FYHGFKQMQS CLEVTEACVG DVVCNAQLAL YLKACSANGN LCDVKHCQAA IRFFYQNMPF
NTAQMLAFCD CAQSDIPCQQ SKETLHSKPC ALNIVPPPTC LSVIHTCRND ELCRTHYRTF
QTECWPHITG KCHEDETCIS MLGKQDLTCS GSESCRAAFL GTFGTVLQVP CACRGVTQAE
EHVCMIFQHM LHSKSCFNYP TPNVKDISSY EKKNSKEITL TGFNSFFNGE LLYVVVCMAV
TCGILFLVML KLRIQSEKRD PSSIEIAGGV IIQ
