ID GDF15_HUMAN Reviewed; 308 AA. AC Q99988; O14629; P78360; Q9BWA0; Q9NRT0; DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot. DT 30-NOV-2010, sequence version 3. DT 02-SEP-2026, entry version 202. DE RecName: Full=Growth/differentiation factor 15 {ECO:0000303|PubMed:23468844}; DE Short=GDF-15 {ECO:0000303|PubMed:23468844}; DE AltName: Full=Macrophage inhibitory cytokine 1 {ECO:0000303|PubMed:28846099}; DE Short=MIC-1 {ECO:0000303|PubMed:28846099}; DE AltName: Full=NSAID-activated gene 1 protein; DE Short=NAG-1; DE AltName: Full=NSAID-regulated gene 1 protein; DE Short=NRG-1; DE AltName: Full=Placental TGF-beta {ECO:0000303|PubMed:9375789}; DE AltName: Full=Placental bone morphogenetic protein {ECO:0000303|PubMed:9375789}; DE AltName: Full=Prostate differentiation factor {ECO:0000303|PubMed:9593718}; DE Flags: Precursor; GN Name=GDF15 {ECO:0000303|PubMed:23468844, ECO:0000312|HGNC:HGNC:30142}; GN Synonyms=MIC1 {ECO:0000303|PubMed:28846099}, PDF GN {ECO:0000303|PubMed:9593718}, PLAB {ECO:0000303|PubMed:9375789}, GN PTGFB; 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], AND VARIANT ASP-202. RC TISSUE=Placenta; RX PubMed=9375789; DOI=10.1016/s0167-4781(97)00122-x; RA Hromas R., Hufford M., Sutton J., Xu D., Li Y., Lu L.; RT "PLAB, a novel placental bone morphogenetic protein."; RL Biochim. Biophys. Acta 1354:40-44(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], VARIANTS LEU-9 AND THR-48, AND TISSUE RP SPECIFICITY. RC TISSUE=Fibrosarcoma; RX PubMed=9348093; DOI=10.1093/oxfordjournals.jbchem.a021798; RA Yokoyama-Kobayashi M., Saeki M., Sekine S., Kato S.; RT "Human cDNA encoding a novel TGF-beta superfamily protein highly expressed RT in placenta."; RL J. Biochem. 122:622-626(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS LEU-9 AND THR-48. RX PubMed=9326641; DOI=10.1073/pnas.94.21.11514; RA Bootcov M.R., Bauskin A.R., Valenzuela S.M., Moore A.G., Bansal M., RA He X.Y., Zhang H.P., Donnellan M., Mahler S., Pryor K., Walsh B.J., RA Nicholson R.C., Fairlie W.D., Por S.B., Robbins J.M., Breit S.N.; RT "MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of RT the TGF-beta superfamily."; RL Proc. Natl. Acad. Sci. U.S.A. 94:11514-11519(1997). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT LEU-9. RC TISSUE=Placenta; RX PubMed=9593718; DOI=10.1074/jbc.273.22.13760; RA Paralkar V.M., Vail A.L., Grasser W.A., Brown T.A., Xu H., Vukicevic S., RA Ke H.Z., Qi H., Owen T.A., Thompson D.D.; RT "Cloning and characterization of a novel member of the transforming growth RT factor-beta/bone morphogenetic protein family."; RL J. Biol. Chem. 273:13760-13767(1998). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS LEU-9 AND THR-48. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Placenta; 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 [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [8] 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 [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Muscle; 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 [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 14-308. RX PubMed=9426002; DOI=10.1016/s0378-1119(97)00485-x; RA Lawton L.N., de Fatima Bonaldo M., Jelenc P.C., Qiu L., Baumes S.A., RA Marcelino R.A., de Jesus G.M., Wellington S., Knowles J.A., Warburton D., RA Brown S., Soares M.B.; RT "Identification of a novel member of the TGF-beta superfamily highly RT expressed in human placenta."; RL Gene 203:17-26(1997). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 264-308. RX PubMed=11259636; DOI=10.1124/mol.59.4.901; RA Baek S.J., Kim K.S., Nixon J.B., Wilson L.C., Eling T.E.; RT "Cyclooxygenase inhibitors regulate the expression of a TGF-beta RT superfamily member that has proapoptotic and antitumorigenic activities."; RL Mol. Pharmacol. 59:901-908(2001). RN [12] RP FUNCTION. RX PubMed=23468844; DOI=10.1371/journal.pone.0055174; RA Tsai V.W., Macia L., Johnen H., Kuffner T., Manadhar R., Joergensen S.B., RA Lee-Ng K.K., Zhang H.P., Wu L., Marquis C.P., Jiang L., Husaini Y., Lin S., RA Herzog H., Brown D.A., Sainsbury A., Breit S.N.; RT "TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and RT body weight regulator."; RL PLoS ONE 8:E55174-E55174(2013). RN [13] RP FUNCTION. RX PubMed=24971956; DOI=10.1371/journal.pone.0100370; RA Tsai V.W., Manandhar R., Joergensen S.B., Lee-Ng K.K., Zhang H.P., RA Marquis C.P., Jiang L., Husaini Y., Lin S., Sainsbury A., Sawchenko P.E., RA Brown D.A., Breit S.N.; RT "The anorectic actions of the TGFbeta cytokine MIC-1/GDF15 require an RT intact brainstem area postrema and nucleus of the solitary tract."; RL PLoS ONE 9:e100370-e100370(2014). RN [14] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=28572090; DOI=10.15252/emmm.201707604; RA Wang T., Liu J., McDonald C., Lupino K., Zhai X., Wilkins B.J., RA Hakonarson H., Pei L.; RT "GDF15 is a heart-derived hormone that regulates body growth."; RL EMBO Mol. Med. 9:1150-1164(2017). RN [15] RP FUNCTION, INTERACTION WITH GFRAL, AND MUTAGENESIS OF TRP-225 AND ILE-285. 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 [16] RP FUNCTION, INTERACTION WITH GFRAL, AND MUTAGENESIS OF VAL-283. 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 [17] RP FUNCTION, AND INTERACTION WITH GFRAL. 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 [18] RP INVOLVEMENT IN HG. RX PubMed=29563502; DOI=10.1038/s41467-018-03258-0; RG 23andMe Research Team; RA Fejzo M.S., Sazonova O.V., Sathirapongsasuti J.F., Hallgrimsdottir I.B., RA Vacic V., MacGibbon K.W., Schoenberg F.P., Mancuso N., Slamon D.J., RA Mullin P.M.; RT "Placenta and appetite genes GDF15 and IGFBP7 are associated with RT hyperemesis gravidarum."; RL Nat. Commun. 9:1178-1178(2018). RN [19] RP FUNCTION, AND INDUCTION. RX PubMed=31402172; DOI=10.1016/j.cell.2019.07.033; RA Luan H.H., Wang A., Hilliard B.K., Carvalho F., Rosen C.E., Ahasic A.M., RA Herzog E.L., Kang I., Pisani M.A., Yu S., Zhang C., Ring A.M., Young L.H., RA Medzhitov R.; RT "GDF15 is an inflammation-induced central mediator of tissue tolerance."; RL Cell 178:1231-1244(2019). RN [20] RP FUNCTION, AND INDUCTION. RX PubMed=30639358; DOI=10.1016/j.cmet.2018.12.016; RA Patel S., Alvarez-Guaita A., Melvin A., Rimmington D., Dattilo A., RA Miedzybrodzka E.L., Cimino I., Maurin A.C., Roberts G.P., Meek C.L., RA Virtue S., Sparks L.M., Parsons S.A., Redman L.M., Bray G.A., Liou A.P., RA Woods R.M., Parry S.A., Jeppesen P.B., Kolnes A.J., Harding H.P., Ron D., RA Vidal-Puig A., Reimann F., Gribble F.M., Hulston C.J., Farooqi I.S., RA Fafournoux P., Smith S.R., Jensen J., Breen D., Wu Z., Zhang B.B., RA Coll A.P., Savage D.B., O'Rahilly S.; RT "GDF15 provides an endocrine signal of nutritional stress in mice and RT humans."; RL Cell Metab. 29:707-718(2019). RN [21] RP SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=32694673; DOI=10.1038/s42255-019-0146-4; RA Day E.A., Ford R.J., Smith B.K., Mohammadi-Shemirani P., Morrow M.R., RA Gutgesell R.M., Lu R., Raphenya A.R., Kabiri M., McArthur A.G., McInnes N., RA Hess S., Pare G., Gerstein H.C., Steinberg G.R.; RT "Metformin-induced increases in GDF15 are important for suppressing RT appetite and promoting weight loss."; RL Nat. Metab. 1:1202-1208(2019). RN [22] RP INDUCTION. RX PubMed=33207247; DOI=10.1016/j.cmet.2020.10.023; RA Breen D.M., Kim H., Bennett D., Calle R.A., Collins S., Esquejo R.M., RA He T., Joaquim S., Joyce A., Lambert M., Lin L., Pettersen B., Qiao S., RA Rossulek M., Weber G., Wu Z., Zhang B.B., Birnbaum M.J.; RT "GDF-15 neutralization alleviates platinum-based chemotherapy-induced RT emesis, anorexia, and weight loss in mice and nonhuman primates."; RL Cell Metab. 32:938-950(2020). RN [23] RP FUNCTION, SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=31875646; DOI=10.1038/s41586-019-1911-y; RA Coll A.P., Chen M., Taskar P., Rimmington D., Patel S., Tadross J.A., RA Cimino I., Yang M., Welsh P., Virtue S., Goldspink D.A., RA Miedzybrodzka E.L., Konopka A.R., Esponda R.R., Huang J.T., Tung Y.C.L., RA Rodriguez-Cuenca S., Tomaz R.A., Harding H.P., Melvin A., Yeo G.S.H., RA Preiss D., Vidal-Puig A., Vallier L., Nair K.S., Wareham N.J., Ron D., RA Gribble F.M., Reimann F., Sattar N., Savage D.B., Allan B.B., O'Rahilly S.; RT "GDF15 mediates the effects of metformin on body weight and energy RT balance."; RL Nature 578:444-448(2020). RN [24] RP FUNCTION. RX PubMed=32661391; DOI=10.1038/s41591-020-0945-x; RA Suriben R., Chen M., Higbee J., Oeffinger J., Ventura R., Li B., Mondal K., RA Gao Z., Ayupova D., Taskar P., Li D., Starck S.R., Chen H.H., McEntee M., RA Katewa S.D., Phung V., Wang M., Kekatpure A., Lakshminarasimhan D., RA White A., Olland A., Haldankar R., Solloway M.J., Hsu J.Y., Wang Y., RA Tang J., Lindhout D.A., Allan B.B.; RT "Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer RT cachexia in mice."; RL Nat. Med. 26:1264-1270(2020). RN [25] RP FUNCTION. RX PubMed=33589633; DOI=10.1038/s41467-021-21309-x; RA Klein A.B., Nicolaisen T.S., Oertenblad N., Gejl K.D., Jensen R., RA Fritzen A.M., Larsen E.L., Karstoft K., Poulsen H.E., Morville T., RA Sahl R.E., Helge J.W., Lund J., Falk S., Lyngbaek M., Ellingsgaard H., RA Pedersen B.K., Lu W., Finan B., Joergensen S.B., Seeley R.J., Kleinert M., RA Kiens B., Richter E.A., Clemmensen C.; RT "Pharmacological but not physiological GDF15 suppresses feeding and the RT motivation to exercise."; RL Nat. Commun. 12:1041-1041(2021). RN [26] RP VARIANT HG GLY-211. RX PubMed=35218128; DOI=10.1111/1471-0528.17129; RA Fejzo M.S., MacGibbon K.W., First O., Quan C., Mullin P.M.; RT "Whole-exome sequencing uncovers new variants in GDF15 associated with RT hyperemesis gravidarum."; RL BJOG 129:1845-1852(2022). RN [27] RP INDUCTION. RX PubMed=38056430; DOI=10.1016/j.cmet.2023.11.003; RA Lu J.F., Zhu M.Q., Xia B., Zhang N.N., Liu X.P., Liu H., Zhang R.X., RA Xiao J.Y., Yang H., Zhang Y.Q., Li X.M., Wu J.W.; RT "GDF15 is a major determinant of ketogenic diet-induced weight loss."; RL Cell Metab. 35:2165-2182(2023). RN [28] RP FUNCTION, AND INDUCTION. RX PubMed=36001956; DOI=10.1016/j.celrep.2022.111258; RA Klein A.B., Nicolaisen T.S., Johann K., Fritzen A.M., Mathiesen C.V., RA Gil C., Pilmark N.S., Karstoft K., Blond M.B., Quist J.S., Seeley R.J., RA Faerch K., Lund J., Kleinert M., Clemmensen C.; RT "The GDF15-GFRAL pathway is dispensable for the effects of metformin on RT energy balance."; RL Cell Rep. 40:111258-111258(2022). RN [29] RP POSSIBLE ROLE IN THE TREATMENT OF OBESITY. RX PubMed=36630958; DOI=10.1016/j.cmet.2022.12.011; RA Benichou O., Coskun T., Gonciarz M.D., Garhyan P., Adams A.C., Du Y., RA Dunbar J.D., Martin J.A., Mather K.J., Pickard R.T., Reynolds V.L., RA Robins D.A., Zvada S.P., Emmerson P.J.; RT "Discovery, development, and clinical proof of mechanism of LY3463251, a RT long-acting GDF15 receptor agonist."; RL Cell Metab. 35:274-286(2023). RN [30] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=37060902; DOI=10.1016/j.cmet.2023.03.014; RA Zhang S.Y., Bruce K., Danaei Z., Li R.J.W., Barros D.R., Kuah R., Lim Y.M., RA Mariani L.H., Cherney D.Z., Chiu J.F.M., Reich H.N., Lam T.K.T.; RT "Metformin triggers a kidney GDF15-dependent area postrema axis to regulate RT food intake and body weight."; RL Cell Metab. 35:875-886(2023). RN [31] RP FUNCTION, SUBCELLULAR LOCATION, VARIANT ASP-202, VARIANT HG GLY-211, AND RP CHARACTERIZATION OF VARIANT HG GLY-211. RX PubMed=38092039; DOI=10.1038/s41586-023-06921-9; RA Fejzo M., Rocha N., Cimino I., Lockhart S.M., Petry C.J., Kay R.G., RA Burling K., Barker P., George A.L., Yasara N., Premawardhena A., Gong S., RA Cook E., Rimmington D., Rainbow K., Withers D.J., Cortessis V., RA Mullin P.M., MacGibbon K.W., Jin E., Kam A., Campbell A., Polasek O., RA Tzoneva G., Gribble F.M., Yeo G.S.H., Lam B.Y.H., Saudek V., Hughes I.A., RA Ong K.K., Perry J.R.B., Sutton Cole A., Baumgarten M., Welsh P., Sattar N., RA Smith G.C.S., Charnock-Jones D.S., Coll A.P., Meek C.L., Mettananda S., RA Hayward C., Mancuso N., O'Rahilly S.; RT "GDF15 linked to maternal risk of nausea and vomiting during pregnancy."; RL Nature 0:0-0(2023). RN [32] {ECO:0007744|PDB:5VZ3, ECO:0007744|PDB:5VZ4} RP X-RAY CRYSTALLOGRAPHY (1.97 ANGSTROMS) OF 197-308 IN COMPLEX WITH GFRAL, RP INTERACTION WITH GFRAL, FUNCTION, AND MUTAGENESIS OF VAL-283 AND ILE-285. 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 [33] 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 [34] {ECO:0007744|PDB:5VT2} RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 197-308, FUNCTION, SUBUNIT, RP INDUCTION BY OBESITY, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=29046435; DOI=10.1126/scitranslmed.aan8732; RA Xiong Y., Walker K., Min X., Hale C., Tran T., Komorowski R., Yang J., RA Davda J., Nuanmanee N., Kemp D., Wang X., Liu H., Miller S., Lee K.J., RA Wang Z., Veniant M.M.; RT "Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to RT monkeys."; RL Sci. Transl. Med. 9:0-0(2017). RN [35] {ECO:0007744|PDB:6Q2J} RP STRUCTURE BY ELECTRON MICROSCOPY (4.10 ANGSTROMS) OF 197-308 IN COMPLEX RP WITH RET AND GFRAL, FUNCTION, SUBUNIT, DISULFIDE BONDS, INTERACTION WITH RP GFRAL, AND MUTAGENESIS OF TRP-228 AND TYR-297. RX PubMed=31535977; DOI=10.7554/elife.47650; RA Li J., Shang G., Chen Y.J., Brautigam C.A., Liou J., Zhang X., Bai X.C.; RT "Cryo-EM analyses reveal the common mechanism and diversification in the RT activation of RET by different ligands."; RL Elife 8:0-0(2019). CC -!- FUNCTION: Hormone produced in response to various stresses to confer CC information about those stresses to the brain, and trigger an aversive CC response, characterized by nausea, vomiting, and/or loss of appetite CC (PubMed:23468844, PubMed:24971956, PubMed:28846097, PubMed:28846098, CC PubMed:28846099, PubMed:28953886, PubMed:29046435, PubMed:30639358, CC PubMed:31875646, PubMed:33589633, PubMed:38092039). The aversive CC response is both required to reduce continuing exposure to those CC stresses at the time of exposure and to promote avoidance behavior in CC the future (PubMed:30639358, PubMed:33589633, PubMed:38092039). Acts by CC binding to its receptor, GFRAL, activating GFRAL-expressing neurons CC localized in the area postrema and nucleus tractus solitarius of the CC brainstem (PubMed:28846097, PubMed:28846098, PubMed:28846099, CC PubMed:28953886, PubMed:31535977). It then triggers the activation of CC neurons localized within the parabrachial nucleus and central amygdala, CC which constitutes part of the 'emergency circuit' that shapes responses CC to stressful conditions (PubMed:28953886). The GDF15-GFRAL signal CC induces expression of genes involved in metabolism, such as lipid CC metabolism in adipose tissues (PubMed:31402172). Required for avoidance CC behavior in response to food allergens: induced downstream of mast cell CC activation to promote aversion and minimize harmful effects of exposure CC to noxious substances (By similarity). In addition to suppress CC appetite, also promotes weight loss by enhancing energy expenditure in CC muscle: acts by increasing calcium futile cycling in muscle (By CC similarity). Contributes to the effect of metformin, an anti-diabetic CC drug, on appetite reduction and weight loss: produced in the kidney in CC response to metformin treatment, thereby activating the GDF15-GFRAL CC response, leading to reduced appetite and weight (PubMed:31875646, CC PubMed:37060902). The contribution of GDF15 to weight loss following CC metformin treatment is however limited and subject to discussion CC (PubMed:36001956). Produced in response to anticancer drugs, such as CC camptothecin or cisplatin, promoting nausea, vomiting and contributing CC to malnutrition (By similarity). Overproduced in many cancers, CC promoting anorexia in cancer (cachexia) (PubMed:32661391). Responsible CC for the risk of nausea and vomiting during pregnancy: high levels of CC GDF15 during pregnancy, mostly originating from the fetus, are CC associated with increased nausea and vomiting (PubMed:38092039). CC Maternal sensitivity to nausea is probably determined by pre-pregnancy CC exposure to GDF15, women with naturally high level of GDF15 being less CC susceptible to nausea than women with low levels of GDF15 before CC pregnancy (PubMed:38092039). Promotes metabolic adaptation in response CC to systemic inflammation caused by bacterial and viral infections in CC order to promote tissue tolerance and prevent tissue damage CC (PubMed:31402172). Required for tissue tolerance in response to CC myocardial infarction by acting as an inhibitor of leukocyte integring CC activation, thereby protecting against cardiac rupture (By similarity). CC Inhibits growth hormone signaling on hepatocytes (By similarity). CC {ECO:0000250|UniProtKB:Q9Z0J7, ECO:0000269|PubMed:23468844, CC ECO:0000269|PubMed:24971956, ECO:0000269|PubMed:28846097, CC ECO:0000269|PubMed:28846098, ECO:0000269|PubMed:28846099, CC ECO:0000269|PubMed:28953886, ECO:0000269|PubMed:29046435, CC ECO:0000269|PubMed:30639358, ECO:0000269|PubMed:31402172, CC ECO:0000269|PubMed:31535977, ECO:0000269|PubMed:31875646, CC ECO:0000269|PubMed:32661391, ECO:0000269|PubMed:33589633, CC ECO:0000269|PubMed:36001956, ECO:0000269|PubMed:37060902, CC ECO:0000269|PubMed:38092039}. CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:29046435, CC PubMed:31535977). Interacts with GFRAL and RET; ligand of GFRAL, which CC mediates GDF15 internalization and cellular signaling through CC interaction with RET via the formation of a 2:2:2 ternary complex CC composed of GDF15, GFRAL and RET (PubMed:28846097, PubMed:28846098, CC PubMed:28846099, PubMed:28953886, PubMed:31535977). CC {ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846098, CC ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886, CC ECO:0000269|PubMed:29046435, ECO:0000269|PubMed:31535977}. CC -!- INTERACTION: CC Q99988; Q13185: CBX3; NbExp=3; IntAct=EBI-2116863, EBI-78176; CC Q99988; Q6UXV0: GFRAL; NbExp=2; IntAct=EBI-2116863, EBI-27112718; CC Q99988; P49639: HOXA1; NbExp=3; IntAct=EBI-2116863, EBI-740785; CC Q99988; P59991: KRTAP12-2; NbExp=3; IntAct=EBI-2116863, EBI-10176379; CC Q99988; Q99750: MDFI; NbExp=5; IntAct=EBI-2116863, EBI-724076; CC Q99988; Q9Y6A5: TACC3; NbExp=3; IntAct=EBI-2116863, EBI-2554984; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:28572090, CC ECO:0000269|PubMed:29046435, ECO:0000269|PubMed:31875646, CC ECO:0000269|PubMed:32694673, ECO:0000269|PubMed:38092039}. CC Note=Secreted in the plasma. {ECO:0000269|PubMed:28572090, CC ECO:0000269|PubMed:29046435}. CC -!- TISSUE SPECIFICITY: Detected in plasma (at protein level) CC (PubMed:28572090, PubMed:29046435). Highly expressed in placenta, with CC lower levels in prostate and colon and some expression in kidney CC (PubMed:37060902, PubMed:9348093). {ECO:0000269|PubMed:28572090, CC ECO:0000269|PubMed:29046435, ECO:0000269|PubMed:37060902, CC ECO:0000269|PubMed:9348093}. CC -!- INDUCTION: Produced in response to various stresses, such as metabolic CC and toxin-induced stresses or drugs (PubMed:31402172, PubMed:31875646, CC PubMed:32694673, PubMed:33207247, PubMed:33589633, PubMed:36001956). CC Expression is activated by ATF4 and DDIT3/CHOP transcription factors CC downstream of the integrated stress response (ISR) (PubMed:30639358). CC Expressed in response to inflammatory conditions (PubMed:31402172). CC Expression is induced by metformin, a blood-glucose-lowering drug CC (PubMed:31875646, PubMed:32694673, PubMed:36001956). Expression is CC induced by cisplatin anticancer drug (PubMed:33207247). Also induced by CC physical activity (PubMed:33589633). Expression is up-regulated by CC obesity (PubMed:29046435). Expression is up-regulated by ketogenic diet CC (PubMed:38056430). {ECO:0000269|PubMed:29046435, CC ECO:0000269|PubMed:30639358, ECO:0000269|PubMed:31402172, CC ECO:0000269|PubMed:31875646, ECO:0000269|PubMed:32694673, CC ECO:0000269|PubMed:33207247, ECO:0000269|PubMed:33589633, CC ECO:0000269|PubMed:36001956, ECO:0000269|PubMed:38056430}. CC -!- DISEASE: Hyperemesis gravidarum (HG) [MIM:620730]: An autosomal CC dominant condition characterized by severe nausea and vomiting in CC pregnancy. It occurs in up to 2% of pregnancies and leads to CC significant weight loss, dehydration, electrolyte imbalance, and CC ketonuria. It is associated with both maternal and fetal morbidity. CC {ECO:0000269|PubMed:29563502, ECO:0000269|PubMed:35218128, CC ECO:0000269|PubMed:38092039}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: GDF15 was initially considered as a promising factor for CC the treatment of obesity due to its ability of GDF15 to reduce appetite CC and promote weight loss (PubMed:31875646). However, while activation of CC the GDF15-GFRAL signaling pathway is efficient to reduce obesity and CC promote weight loss in mouse, it only has limited effect in human CC (PubMed:36630958). {ECO:0000269|PubMed:31875646, CC ECO:0000269|PubMed:36630958}. CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/40701/GDF15"; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Nausea - Issue 270 of July CC 2024; CC URL="https://www.proteinspotlight.org/back_issues/270/"; 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; U88323; AAB88913.1; -; mRNA. DR EMBL; AB000584; BAA19151.1; -; mRNA. DR EMBL; AF019770; AAB88673.1; -; mRNA. DR EMBL; AF003934; AAC24456.1; -; mRNA. DR EMBL; AK291530; BAF84219.1; -; mRNA. DR EMBL; BT019465; AAV38272.1; -; mRNA. DR EMBL; AC008397; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471106; EAW84694.1; -; Genomic_DNA. DR EMBL; BC000529; AAH00529.1; -; mRNA. DR EMBL; BC008962; AAH08962.1; -; mRNA. DR EMBL; AF008303; AAC39537.1; -; Genomic_DNA. DR EMBL; AF173860; AAF89834.1; -; mRNA. DR CCDS; CCDS12376.1; -. DR PIR; JC5697; JC5697. DR RefSeq; NP_004855.2; NM_004864.4. DR PDB; 5VT2; X-ray; 2.30 A; A/B=197-308. DR PDB; 5VZ3; X-ray; 1.97 A; A=197-308. DR PDB; 5VZ4; X-ray; 2.20 A; A=197-308. DR PDB; 6Q2J; EM; 4.10 A; A/B=197-308. DR AlphaFoldDB; Q99988; -. DR EMDB; EMD-11777; -. DR EMDB; EMD-20572; -. DR SMR; Q99988; -. DR BioGRID; 114895; 99. DR CORUM; Q99988; -. DR FunCoup; Q99988; 800. DR IntAct; Q99988; 71. DR MINT; Q99988; -. DR NDEx; IQUERY-CP-GDF15; 7 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000252809; -. DR ChEMBL; CHEMBL3120039; -. DR GlyCosmos; Q99988; 1 site, No reported glycans. DR GlyGen; Q99988; 7 sites, 2 N-linked glycans (1 site), 2 O-linked glycans (5 sites). DR iPTMnet; Q99988; -. DR PhosphoSitePlus; Q99988; -. DR SwissPalm; Q99988; -. DR BioMuta; GDF15; -. DR DMDM; 313104195; -. DR jPOST; Q99988; -. DR MassIVE; Q99988; -. DR PaxDb; 9606-ENSP00000252809; -. DR PeptideAtlas; Q99988; -. DR ProteomicsDB; 78564; -. DR Pumba; Q99988; -. DR Antibodypedia; 2781; 1027 antibodies from 46 providers. DR DNASU; 9518; -. DR Ensembl; ENST00000252809.3; ENSP00000252809.3; ENSG00000130513.7. DR Ensembl; ENST00000595973.3; ENSP00000470531.3; ENSG00000130513.7. DR Ensembl; ENST00000597765.2; ENSP00000469819.2; ENSG00000130513.7. DR GeneID; 9518; -. DR KEGG; hsa:9518; -. DR MANE-Select; ENST00000252809.3; ENSP00000252809.3; NM_004864.4; NP_004855.2. DR UCSC; uc002niv.2; human. DR AGR; HGNC:30142; -. DR ClinPGx; PA134866647; -. DR CTD; 9518; -. DR DisGeNET; 9518; -. DR GeneCards; GDF15; -. DR HGNC; HGNC:30142; GDF15. DR HPA; ENSG00000130513; Tissue enhanced (kidney). DR MalaCards; GDF15; -. DR MIM; 605312; gene. DR MIM; 620730; phenotype. DR OpenTargets; ENSG00000130513; -. DR VEuPathDB; HostDB:ENSG00000130513; -. DR eggNOG; KOG3900; Eukaryota. DR GeneTree; ENSGT00940000161872; -. DR HOGENOM; CLU_064099_1_0_1; -. DR InParanoid; Q99988; -. DR OMA; DHCPLGP; -. DR OrthoDB; 10030979at2759; -. DR PAN-GO; Q99988; 6 GO annotations based on evolutionary models. DR PhylomeDB; Q99988; -. DR PathwayCommons; Q99988; -. DR SignaLink; Q99988; -. DR SIGNOR; Q99988; -. DR Agora; ENSG00000130513; -. DR BioGRID-ORCS; 9518; 6 hits in 1162 CRISPR screens. DR ChiTaRS; GDF15; human. DR GeneWiki; GDF15; -. DR GenomeRNAi; 9518; -. DR Pharos; Q99988; Tbio. DR PRO; PR:Q99988; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; Q99988; protein. DR Bgee; ENSG00000130513; Expressed in metanephros cortex and 132 other cell types or tissues. DR ExpressionAtlas; Q99988; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005125; F:cytokine activity; IDA:UniProtKB. DR GO; GO:0008083; F:growth factor activity; IEA:InterPro. DR GO; GO:0005179; F:hormone activity; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0007178; P:cell surface receptor protein serine/threonine kinase signaling pathway; IBA:GO_Central. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:0062197; P:cellular response to chemical stress; IEA:Ensembl. DR GO; GO:0160144; P:GDF15-GFRAL signaling pathway; IDA:UniProtKB. DR GO; GO:0032099; P:negative regulation of appetite; IDA:UniProtKB. DR GO; GO:0060400; P:negative regulation of growth hormone receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0002686; P:negative regulation of leukocyte migration; IEA:Ensembl. DR GO; GO:0040015; P:negative regulation of multicellular organism growth; ISS:UniProtKB. DR GO; GO:0060392; P:negative regulation of SMAD protein signal transduction; IDA:UniProtKB. DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:GO_Central. DR GO; GO:0046321; P:positive regulation of fatty acid oxidation; IEA:Ensembl. DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:GO_Central. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:UniProtKB. DR GO; GO:0002023; P:reduction of food intake in response to dietary excess; IDA:UniProtKB. DR GO; GO:1901558; P:response to metformin; IDA:UniProtKB. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:ProtInc. DR CDD; cd19376; TGF_beta_GDF15; 1. DR FunFam; 2.10.90.10:FF:000039; growth/differentiation factor 15; 1. DR Gene3D; 2.10.90.10; Cystine-knot cytokines; 1. DR InterPro; IPR029034; Cystine-knot_cytokine. DR InterPro; IPR001839; TGF-b_C. DR InterPro; IPR015615; TGF-beta-like. DR PANTHER; PTHR11848:SF78; GROWTH_DIFFERENTIATION FACTOR 15; 1. DR PANTHER; PTHR11848; TGF-BETA FAMILY; 1. DR Pfam; PF00019; TGF_beta; 1. DR SMART; SM00204; TGFB; 1. DR SUPFAM; SSF57501; Cystine-knot cytokines; 1. DR PROSITE; PS51362; TGF_BETA_2; 1. DR PDBsum; 5VT2; -. DR PDBsum; 5VZ3; -. DR PDBsum; 5VZ4; -. DR PDBsum; 6Q2J; -. PE 1: Evidence at protein level; KW 3D-structure; Cleavage on pair of basic residues; Cytokine; KW Disease variant; Disulfide bond; Glycoprotein; Hormone; KW Proteomics identification; Reference proteome; Secreted; Signal. FT SIGNAL 1..29 FT /evidence="ECO:0000255" FT PROPEP 30..194 FT /evidence="ECO:0000255" FT /id="PRO_0000033992" FT CHAIN 195..308 FT /note="Growth/differentiation factor 15" FT /id="PRO_0000033993" FT REGION 152..177 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 165..177 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 70 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 203..210 FT /evidence="ECO:0000269|PubMed:28953886, FT ECO:0000269|PubMed:29046435, ECO:0000269|PubMed:31535977, FT ECO:0007744|PDB:5VT2, ECO:0007744|PDB:5VZ3, FT ECO:0007744|PDB:5VZ4, ECO:0007744|PDB:6Q2J" FT DISULFID 211..274 FT /evidence="ECO:0000269|PubMed:28953886, FT ECO:0000269|PubMed:29046435, ECO:0000269|PubMed:31535977, FT ECO:0007744|PDB:5VT2, ECO:0007744|PDB:5VZ3, FT ECO:0007744|PDB:5VZ4, ECO:0007744|PDB:6Q2J" FT DISULFID 240..305 FT /evidence="ECO:0000269|PubMed:28953886, FT ECO:0000269|PubMed:29046435, ECO:0000269|PubMed:31535977, FT ECO:0007744|PDB:5VT2, ECO:0007744|PDB:5VZ3, FT ECO:0007744|PDB:5VZ4, ECO:0007744|PDB:6Q2J" FT DISULFID 244..307 FT /evidence="ECO:0000269|PubMed:28953886, FT ECO:0000269|PubMed:29046435, ECO:0000269|PubMed:31535977, FT ECO:0007744|PDB:5VT2, ECO:0007744|PDB:5VZ3, FT ECO:0007744|PDB:5VZ4, ECO:0007744|PDB:6Q2J" FT DISULFID 273 FT /note="Interchain" FT /evidence="ECO:0000269|PubMed:29046435, FT ECO:0000269|PubMed:31535977, ECO:0007744|PDB:5VT2, FT ECO:0007744|PDB:6Q2J" FT VARIANT 9 FT /note="V -> L (in dbSNP:rs1059519)" FT /evidence="ECO:0000269|PubMed:9326641, FT ECO:0000269|PubMed:9348093, ECO:0000269|PubMed:9593718, FT ECO:0000269|Ref.5" FT /id="VAR_047646" FT VARIANT 48 FT /note="S -> T (in dbSNP:rs1059369)" FT /evidence="ECO:0000269|PubMed:9326641, FT ECO:0000269|PubMed:9348093, ECO:0000269|Ref.5" FT /id="VAR_010386" FT VARIANT 202 FT /note="H -> D (in dbSNP:rs1058587)" FT /evidence="ECO:0000269|PubMed:38092039, FT ECO:0000269|PubMed:9375789" FT /id="VAR_047647" FT VARIANT 211 FT /note="C -> G (in HG; impaired secretion, the mature FT peptide is not secreted and the unprocessed pro-peptide is FT retained intracellularly; dbSNP:rs372120002)" FT /evidence="ECO:0000269|PubMed:35218128, FT ECO:0000269|PubMed:38092039" FT /id="VAR_088885" FT MUTAGEN 225 FT /note="W->A: No effect on interaction with GFRAL. FT Attenuates GDF15-mediated food-intake inhibition." FT /evidence="ECO:0000269|PubMed:28846097" FT MUTAGEN 228 FT /note="W->E: Abolished formation of a ternary complex with FT GFRAL and RET." FT /evidence="ECO:0000269|PubMed:31535977" FT MUTAGEN 283 FT /note="V->A: Reduces cellular signaling mediated by GFRAL FT and RET." FT /evidence="ECO:0000269|PubMed:28953886" FT MUTAGEN 283 FT /note="V->R: Abolishes interaction with GFRAL. Abolishes FT RET phosphorylation and cellular signaling mediated by FT GFRAL and RET." FT /evidence="ECO:0000269|PubMed:28846099" FT MUTAGEN 285 FT /note="I->A: Reduces cellular signaling mediated by GFRAL FT and RET. Abolishes interaction with GFRAL and FT GDF15-mediated food-intake inhibition." FT /evidence="ECO:0000269|PubMed:28846097, FT ECO:0000269|PubMed:28953886" FT MUTAGEN 297 FT /note="Y->E: Abolished formation of a ternary complex with FT GFRAL and RET." FT /evidence="ECO:0000269|PubMed:31535977" FT CONFLICT 269 FT /note="V -> E (in Ref. 1; AAB88913)" FT /evidence="ECO:0000305" FT CONFLICT 288 FT /note="T -> A (in Ref. 10; AAF89834)" FT /evidence="ECO:0000305" FT STRAND 204..219 FT /evidence="ECO:0007829|PDB:5VZ3" FT HELIX 220..223 FT /evidence="ECO:0007829|PDB:5VZ3" FT TURN 226..228 FT /evidence="ECO:0007829|PDB:5VZ3" FT STRAND 229..231 FT /evidence="ECO:0007829|PDB:5VZ3" FT STRAND 233..243 FT /evidence="ECO:0007829|PDB:5VZ3" FT STRAND 248..250 FT /evidence="ECO:0007829|PDB:5VZ3" FT HELIX 253..264 FT /evidence="ECO:0007829|PDB:5VZ3" FT TURN 266..268 FT /evidence="ECO:0007829|PDB:5VZ3" FT HELIX 270..272 FT /evidence="ECO:0007829|PDB:5VZ3" FT STRAND 274..287 FT /evidence="ECO:0007829|PDB:5VZ3" FT STRAND 289..307 FT /evidence="ECO:0007829|PDB:5VZ3" SQ SEQUENCE 308 AA; 34140 MW; 2FF3959021B95238 CRC64; MPGQELRTVN GSQMLLVLLV LSWLPHGGAL SLAEASRASF PGPSELHSED SRFRELRKRY EDLLTRLRAN QSWEDSNTDL VPAPAVRILT PEVRLGSGGH LHLRISRAAL PEGLPEASRL HRALFRLSPT ASRSWDVTRP LRRQLSLARP QAPALHLRLS PPPSQSDQLL AESSSARPQL ELHLRPQAAR GRRRARARNG DHCPLGPGRC CRLHTVRASL EDLGWADWVL SPREVQVTMC IGACPSQFRA ANMHAQIKTS LHRLKPDTVP APCCVPASYN PMVLIQKTDT GVSLQTYDDL LAKDCHCI //