GFRAL_HUMAN
ID GFRAL_HUMAN Reviewed; 394 AA.
AC Q6UXV0; Q5VTF6;
DT 13-JUN-2006, integrated into UniProtKB/Swiss-Prot.
DT 13-JUN-2006, sequence version 2.
DT 03-AUG-2022, entry version 125.
DE RecName: Full=GDNF family receptor alpha-like {ECO:0000305};
DE Flags: Precursor;
GN Name=GFRAL {ECO:0000312|HGNC:HGNC:32789}; Synonyms=C6orf144;
GN ORFNames=UNQ9356/PRO34128;
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], AND VARIANT PRO-387.
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
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 FUNCTION, TISSUE SPECIFICITY, AND INTERACTION WITH GDF15 AND RET.
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).
RN [4]
RP FUNCTION, AND INTERACTION WITH GDF15 AND RET.
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 [5]
RP FUNCTION, INTERACTION WITH GDF15, AND TISSUE SPECIFICITY.
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 [6] {ECO:0007744|PDB:5VZ4}
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 115-351 IN COMPLEX WITH GDF15,
RP INTERACTION WITH GDF15 AND RET, SUBCELLULAR LOCATION, AND FUNCTION.
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 [7]
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 [8]
RP VARIANT [LARGE SCALE ANALYSIS] HIS-195.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
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:28846097,
CC PubMed:28846098, PubMed:28846099). Upon interaction with its ligand,
CC GDF15, interacts with RET and induces cellular signaling through
CC activation of MAPK- and AKT- signaling pathways.
CC {ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846098,
CC ECO:0000269|PubMed:28846099, 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:28953886, PubMed:28846097,
CC PubMed:28846099). Interaction with RET requires previous GDF15-binding
CC (PubMed:28846097, PubMed:28846099). {ECO:0000269|PubMed:28846097,
CC ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886}.
CC -!- INTERACTION:
CC Q6UXV0; Q99988: GDF15; NbExp=2; IntAct=EBI-27112718, EBI-2116863;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:28953886};
CC Single-pass membrane protein {ECO:0000269|PubMed:28953886};
CC Extracellular side {ECO:0000269|PubMed:28953886}.
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 (at protein level) (PubMed:28846097,
CC PubMed:28846098). Detected at low levels in testis and adipose tissue
CC (PubMed:28846097). {ECO:0000269|PubMed:28846097,
CC ECO:0000269|PubMed:28846098}.
CC -!- SIMILARITY: Belongs to the GDNFR family. {ECO:0000305}.
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DR EMBL; AY358198; AAQ88565.1; -; mRNA.
DR EMBL; AL592426; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS4957.1; -.
DR RefSeq; NP_997293.2; NM_207410.2.
DR PDB; 5VZ4; X-ray; 2.20 A; B=115-351.
DR PDB; 6Q2J; EM; 4.10 A; C/D=20-352.
DR PDB; 6WMW; X-ray; 2.91 A; B=115-351.
DR PDBsum; 5VZ4; -.
DR PDBsum; 6Q2J; -.
DR PDBsum; 6WMW; -.
DR AlphaFoldDB; Q6UXV0; -.
DR SMR; Q6UXV0; -.
DR BioGRID; 133131; 2.
DR IntAct; Q6UXV0; 1.
DR STRING; 9606.ENSP00000343636; -.
DR GuidetoPHARMACOLOGY; 2977; -.
DR GlyGen; Q6UXV0; 6 sites.
DR BioMuta; GFRAL; -.
DR DMDM; 108935991; -.
DR PaxDb; Q6UXV0; -.
DR PeptideAtlas; Q6UXV0; -.
DR PRIDE; Q6UXV0; -.
DR Antibodypedia; 54700; 146 antibodies from 20 providers.
DR DNASU; 389400; -.
DR Ensembl; ENST00000340465.2; ENSP00000343636.2; ENSG00000187871.2.
DR GeneID; 389400; -.
DR KEGG; hsa:389400; -.
DR MANE-Select; ENST00000340465.2; ENSP00000343636.2; NM_207410.2; NP_997293.2.
DR UCSC; uc003pcm.1; human.
DR CTD; 389400; -.
DR DisGeNET; 389400; -.
DR GeneCards; GFRAL; -.
DR HGNC; HGNC:32789; GFRAL.
DR HPA; ENSG00000187871; Not detected.
DR MIM; 617837; gene.
DR neXtProt; NX_Q6UXV0; -.
DR PharmGKB; PA145008357; -.
DR VEuPathDB; HostDB:ENSG00000187871; -.
DR eggNOG; ENOG502RCJT; Eukaryota.
DR GeneTree; ENSGT00730000111274; -.
DR HOGENOM; CLU_058745_1_0_1; -.
DR InParanoid; Q6UXV0; -.
DR OMA; CLNVIHS; -.
DR OrthoDB; 1089046at2759; -.
DR PhylomeDB; Q6UXV0; -.
DR TreeFam; TF331647; -.
DR PathwayCommons; Q6UXV0; -.
DR BioGRID-ORCS; 389400; 8 hits in 1068 CRISPR screens.
DR GenomeRNAi; 389400; -.
DR Pharos; Q6UXV0; Tbio.
DR PRO; PR:Q6UXV0; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; Q6UXV0; protein.
DR Bgee; ENSG00000187871; Expressed in sural nerve and 4 other tissues.
DR GO; GO:0015629; C:actin cytoskeleton; IDA:HPA.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005925; C:focal adhesion; IDA:HPA.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
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; IDA:UniProtKB.
DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0007399; P:nervous system development; IBA:GO_Central.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:UniProtKB.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IDA:UniProtKB.
DR GO; GO:0002023; P:reduction of food intake in response to dietary excess; ISS:UniProtKB.
DR GO; GO:0031098; P:stress-activated protein kinase signaling cascade; IEA:Ensembl.
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 3D-structure; Cell membrane; Disulfide bond; Glycoprotein; Membrane;
KW Receptor; Reference proteome; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..394
FT /note="GDNF family receptor alpha-like"
FT /id="PRO_0000240124"
FT TOPO_DOM 19..351
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 352..371
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 372..394
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 149..228
FT /note="Required for interaction with GDF15"
FT /evidence="ECO:0000269|PubMed:28846098"
FT CARBOHYD 23
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 50
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 62
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 67
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 103
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 116
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 131..189
FT /evidence="ECO:0000269|PubMed:28953886,
FT ECO:0007744|PDB:5VZ4"
FT DISULFID 138..144
FT /evidence="ECO:0000269|PubMed:28953886,
FT ECO:0007744|PDB:5VZ4"
FT DISULFID 155..167
FT /evidence="ECO:0000269|PubMed:28953886,
FT ECO:0007744|PDB:5VZ4"
FT DISULFID 162..210
FT /evidence="ECO:0000269|PubMed:28953886,
FT ECO:0007744|PDB:5VZ4"
FT DISULFID 191..198
FT /evidence="ECO:0000269|PubMed:28953886,
FT ECO:0007744|PDB:5VZ4"
FT DISULFID 220..291
FT /evidence="ECO:0000269|PubMed:28953886,
FT ECO:0007744|PDB:5VZ4"
FT DISULFID 227..233
FT /evidence="ECO:0000269|PubMed:28953886,
FT ECO:0007744|PDB:5VZ4"
FT DISULFID 244..275
FT /evidence="ECO:0000269|PubMed:28953886,
FT ECO:0007744|PDB:5VZ4"
FT DISULFID 252..258
FT /evidence="ECO:0000269|PubMed:28953886,
FT ECO:0007744|PDB:5VZ4"
FT DISULFID 269..316
FT /evidence="ECO:0000269|PubMed:28953886,
FT ECO:0007744|PDB:5VZ4"
FT DISULFID 293..304
FT /evidence="ECO:0000269|PubMed:28953886,
FT ECO:0007744|PDB:5VZ4"
FT VARIANT 33
FT /note="R -> C (in dbSNP:rs12199003)"
FT /id="VAR_053105"
FT VARIANT 195
FT /note="D -> H (in a breast cancer sample; somatic mutation;
FT dbSNP:rs1224725337)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036234"
FT VARIANT 387
FT /note="S -> P (in dbSNP:rs9370418)"
FT /evidence="ECO:0000269|PubMed:12975309"
FT /id="VAR_053106"
FT HELIX 131..139
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 142..154
FT /evidence="ECO:0007829|PDB:5VZ4"
FT STRAND 156..161
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 164..175
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 180..188
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 196..205
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 208..211
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 220..228
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 231..244
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 246..252
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 256..260
FT /evidence="ECO:0007829|PDB:5VZ4"
FT TURN 264..266
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 273..280
FT /evidence="ECO:0007829|PDB:5VZ4"
FT TURN 281..284
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 286..288
FT /evidence="ECO:0007829|PDB:5VZ4"
FT TURN 298..300
FT /evidence="ECO:0007829|PDB:6WMW"
FT HELIX 301..311
FT /evidence="ECO:0007829|PDB:5VZ4"
FT HELIX 313..315
FT /evidence="ECO:0007829|PDB:5VZ4"
SQ SEQUENCE 394 AA; 44518 MW; 641ED7D67CF87428 CRC64;
MIVFIFLAMG LSLENEYTSQ TNNCTYLREQ CLRDANGCKH AWRVMEDACN DSDPGDPCKM
RNSSYCNLSI QYLVESNFQF KECLCTDDFY CTVNKLLGKK CINKSDNVKE DKFKWNLTTR
SHHGFKGMWS CLEVAEACVG DVVCNAQLAS YLKACSANGN PCDLKQCQAA IRFFYQNIPF
NIAQMLAFCD CAQSDIPCQQ SKEALHSKTC AVNMVPPPTC LSVIRSCQND ELCRRHYRTF
QSKCWQRVTR KCHEDENCIS TLSKQDLTCS GSDDCKAAYI DILGTVLQVQ CTCRTITQSE
ESLCKIFQHM LHRKSCFNYP TLSNVKGMAL YTRKHANKIT LTGFHSPFNG EVIYAAMCMT
VTCGILLLVM VKLRTSRISS KARDPSSIQI PGEL
