ID GDF11_HUMAN Reviewed; 407 AA. AC O95390; Q9UID1; Q9UID2; DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1999, sequence version 1. DT 27-MAR-2024, entry version 177. DE RecName: Full=Growth/differentiation factor 11 {ECO:0000303|PubMed:10391213}; DE Short=GDF-11; DE AltName: Full=Bone morphogenetic protein 11 {ECO:0000303|PubMed:10075854}; DE Short=BMP-11; DE Flags: Precursor; GN Name=GDF11; Synonyms=BMP11 {ECO:0000303|PubMed:10075854}; 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]. RC TISSUE=Fetal brain; RX PubMed=10075854; DOI=10.1006/dbio.1998.9191; RA Gamer L.W., Wolfman N.M., Celeste A.J., Hattersley G., Hewick R., Rosen V.; RT "A novel BMP expressed in developing mouse limb, spinal cord, and tail bud RT is a potent mesoderm inducer in Xenopus embryos."; RL Dev. Biol. 208:222-232(1999). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RX PubMed=10391213; DOI=10.1038/10320; RA McPherron A.C., Lawler A.M., Lee S.-J.; RT "Regulation of anterior/posterior patterning of the axial skeleton by RT growth/differentiation factor 11."; RL Nat. Genet. 22:260-264(1999). RN [3] RP FUNCTION, TISSUE SPECIFICITY, SUBUNIT, PROTEOLYTIC CLEAVAGE AT ARG-298, RP VARIANT VHO GLN-298, CHARACTERIZATION OF VARIANT VHO GLN-298, AND RP INVOLVEMENT IN VHO. RX PubMed=31215115; DOI=10.1002/humu.23793; RA Cox T.C., Lidral A.C., McCoy J.C., Liu H., Cox L.L., Zhu Y., Anderson R.D., RA Moreno Uribe L.M., Anand D., Deng M., Richter C.T., Nidey N.L., RA Standley J.M., Blue E.E., Chong J.X., Smith J.D., Kirk E.P., Venselaar H., RA Krahn K.N., van Bokhoven H., Zhou H., Cornell R.A., Glass I.A., RA Bamshad M.J., Nickerson D.A., Murray J.C., Lachke S.A., Thompson T.B., RA Buckley M.F., Roscioli T.; RT "Mutations in GDF11 and the extracellular antagonist, Follistatin, as a RT likely cause of Mendelian forms of orofacial clefting in humans."; RL Hum. Mutat. 40:1813-1825(2019). RN [4] {ECO:0007744|PDB:5E4G} RP X-RAY CRYSTALLOGRAPHY (1.50 ANGSTROMS) OF 299-407, DISULFIDE BONDS, AND RP SUBUNIT. RX PubMed=26919518; DOI=10.1107/s2053230x16001588; RA Padyana A.K., Vaidialingam B., Hayes D.B., Gupta P., Franti M., RA Farrow N.A.; RT "Crystal structure of human GDF11."; RL Acta Crystallogr. F 72:160-164(2016). RN [5] {ECO:0007744|PDB:5JHW, ECO:0007744|PDB:5UHM} RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 299-407 IN COMPLEX WITH FST, RP DISULFIDE BONDS, AND FUNCTION. RX PubMed=28257634; DOI=10.1186/s12915-017-0350-1; RA Walker R.G., Czepnik M., Goebel E.J., McCoy J.C., Vujic A., Cho M., Oh J., RA Aykul S., Walton K.L., Schang G., Bernard D.J., Hinck A.P., Harrison C.A., RA Martinez-Hackert E., Wagers A.J., Lee R.T., Thompson T.B.; RT "Structural basis for potency differences between GDF8 and GDF11."; RL BMC Biol. 15:19-19(2017). CC -!- FUNCTION: Secreted signal that acts globally to regulate CC anterior/posterior axial patterning during development. May play CC critical roles in patterning both mesodermal and neural tissues (By CC similarity). It is required for proper vertebral patterning and CC orofacial development (PubMed:31215115). Signals through activin CC receptors type-2, ACVR2A and ACVR2B, and activin receptors type-1, CC ACVR1B, ACVR1C and TGFBR1 leading to the phosphorylation of SMAD2 and CC SMAD3 (PubMed:28257634). {ECO:0000250|UniProtKB:Q9Z1W4, CC ECO:0000269|PubMed:28257634, ECO:0000269|PubMed:31215115}. CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:26919518, CC PubMed:31215115). Interacts directly with ACVR2B (By similarity). CC Interacts directly with ACVR2A (By similarity). Interacts with ACVR1B, CC TGFBR1 and ACVR1C in an ACVR2B-dependent manner (By similarity). CC Interacts with FST isoform 2/FS-288 (PubMed:28257634). CC {ECO:0000250|UniProtKB:Q9Z1W4, ECO:0000269|PubMed:26919518, CC ECO:0000269|PubMed:28257634, ECO:0000269|PubMed:31215115}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}. CC -!- TISSUE SPECIFICITY: In the embryo, strong expression is seen in the CC palatal epithelia, including the medial edge epithelial and midline CC epithelial seam of the palatal shelves. Less pronounced expression is CC also seen throughout the palatal shelf and tongue mesenchyme. CC {ECO:0000269|PubMed:31215115}. CC -!- PTM: Synthesized as large precursor molecule that undergoes proteolytic CC cleavage by furin-like proteases (PubMed:31215115). This produces an CC inactive form consisting of the mature C-terminal portion non- CC covalently bound to its cleaved N-terminal propeptide. Activation of CC the mature form requires additional cleavage of the propeptide by a CC tolloid-like metalloproteinase. {ECO:0000250|UniProtKB:Q9Z1W4, CC ECO:0000269|PubMed:31215115}. CC -!- DISEASE: Vertebral hypersegmentation and orofacial anomalies (VHO) CC [MIM:619122]: An autosomal dominant disease characterized by CC supernumerary ribs, supernumerary cervical, thoracic and/or lumbar CC vertebrae, and orofacial anomalies such as cleft lip with or without CC cleft palate in most patients. {ECO:0000269|PubMed:31215115}. Note=The CC disease may be caused by variants affecting the gene represented in CC this entry. CC -!- SIMILARITY: Belongs to the TGF-beta family. {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; AF100907; AAC72852.1; -; mRNA. DR EMBL; AF028333; AAF21630.1; -; mRNA. DR EMBL; AF028334; AAF21631.1; -; Genomic_DNA. DR CCDS; CCDS8891.1; -. DR RefSeq; NP_005802.1; NM_005811.4. DR RefSeq; XP_006719257.1; XM_006719194.3. DR PDB; 5E4G; X-ray; 1.50 A; A=299-407. DR PDB; 5JHW; X-ray; 2.35 A; A/B=299-407. DR PDB; 5UHM; X-ray; 1.90 A; A/B=299-407. DR PDB; 6MAC; X-ray; 2.34 A; A=300-407. DR PDB; 7MRZ; X-ray; 3.00 A; A=299-407. DR PDBsum; 5E4G; -. DR PDBsum; 5JHW; -. DR PDBsum; 5UHM; -. DR PDBsum; 6MAC; -. DR PDBsum; 7MRZ; -. DR AlphaFoldDB; O95390; -. DR SMR; O95390; -. DR BioGRID; 115515; 72. DR IntAct; O95390; 19. DR MINT; O95390; -. DR STRING; 9606.ENSP00000257868; -. DR DrugCentral; O95390; -. DR GlyCosmos; O95390; 1 site, No reported glycans. DR GlyGen; O95390; 2 sites, 1 O-linked glycan (1 site). DR iPTMnet; O95390; -. DR PhosphoSitePlus; O95390; -. DR BioMuta; GDF11; -. DR MassIVE; O95390; -. DR PaxDb; 9606-ENSP00000257868; -. DR PeptideAtlas; O95390; -. DR ProteomicsDB; 50842; -. DR Antibodypedia; 27725; 335 antibodies from 34 providers. DR DNASU; 10220; -. DR Ensembl; ENST00000257868.10; ENSP00000257868.5; ENSG00000135414.10. DR GeneID; 10220; -. DR KEGG; hsa:10220; -. DR MANE-Select; ENST00000257868.10; ENSP00000257868.5; NM_005811.5; NP_005802.1. DR UCSC; uc001shq.4; human. DR AGR; HGNC:4216; -. DR CTD; 10220; -. DR DisGeNET; 10220; -. DR GeneCards; GDF11; -. DR HGNC; HGNC:4216; GDF11. DR HPA; ENSG00000135414; Tissue enhanced (retina). DR MalaCards; GDF11; -. DR MIM; 603936; gene. DR MIM; 619122; phenotype. DR neXtProt; NX_O95390; -. DR OpenTargets; ENSG00000135414; -. DR PharmGKB; PA28631; -. DR VEuPathDB; HostDB:ENSG00000135414; -. DR eggNOG; KOG3900; Eukaryota. DR GeneTree; ENSGT00940000161052; -. DR InParanoid; O95390; -. DR OMA; SPHCCHF; -. DR OrthoDB; 3015718at2759; -. DR PhylomeDB; O95390; -. DR TreeFam; TF318514; -. DR PathwayCommons; O95390; -. DR SignaLink; O95390; -. DR SIGNOR; O95390; -. DR BioGRID-ORCS; 10220; 18 hits in 1163 CRISPR screens. DR ChiTaRS; GDF11; human. DR GeneWiki; GDF11; -. DR GenomeRNAi; 10220; -. DR Pharos; O95390; Tclin. DR PRO; PR:O95390; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; O95390; Protein. DR Bgee; ENSG00000135414; Expressed in pigmented layer of retina and 171 other cell types or tissues. DR ExpressionAtlas; O95390; baseline and differential. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0032991; C:protein-containing complex; IDA:MGI. DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central. DR GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW. DR GO; GO:0035881; P:amacrine cell differentiation; IEA:Ensembl. DR GO; GO:0048593; P:camera-type eye morphogenesis; IEA:Ensembl. DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl. DR GO; GO:0007498; P:mesoderm development; TAS:UniProtKB. DR GO; GO:0001656; P:metanephros development; IEA:Ensembl. DR GO; GO:1902870; P:negative regulation of amacrine cell differentiation; IEA:Ensembl. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl. DR GO; GO:0007399; P:nervous system development; TAS:UniProtKB. DR GO; GO:0060021; P:roof of mouth development; IEA:Ensembl. DR GO; GO:0001501; P:skeletal system development; TAS:UniProtKB. DR GO; GO:0060395; P:SMAD protein signal transduction; IMP:UniProtKB. DR GO; GO:0021512; P:spinal cord anterior/posterior patterning; IEA:Ensembl. DR GO; GO:0072560; P:type B pancreatic cell maturation; IEA:Ensembl. DR GO; GO:0001657; P:ureteric bud development; IEA:Ensembl. DR CDD; cd19388; TGF_beta_GDF8; 1. DR Gene3D; 2.60.120.970; -; 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; IPR001111; TGF-b_propeptide. DR InterPro; IPR015615; TGF-beta-rel. DR InterPro; IPR017948; TGFb_CS. DR PANTHER; PTHR11848:SF166; GROWTH_DIFFERENTIATION FACTOR 11; 1. DR PANTHER; PTHR11848; TGF-BETA FAMILY; 1. DR Pfam; PF00019; TGF_beta; 1. DR Pfam; PF00688; TGFb_propeptide; 1. DR SMART; SM00204; TGFB; 1. DR SUPFAM; SSF57501; Cystine-knot cytokines; 1. DR PROSITE; PS00250; TGF_BETA_1; 1. DR PROSITE; PS51362; TGF_BETA_2; 1. DR Genevisible; O95390; HS. PE 1: Evidence at protein level; KW 3D-structure; Cleavage on pair of basic residues; Cytokine; KW Disease variant; Disulfide bond; Glycoprotein; Growth factor; KW Reference proteome; Secreted; Signal. FT SIGNAL 1..24 FT /evidence="ECO:0000255" FT PROPEP 25..298 FT /evidence="ECO:0000250" FT /id="PRO_0000033986" FT CHAIN 299..407 FT /note="Growth/differentiation factor 11" FT /id="PRO_0000033987" FT SITE 121..122 FT /note="Cleavage; by BMP1" FT /evidence="ECO:0000250|UniProtKB:Q9Z1W4" FT SITE 298 FT /note="Cleavage; by FURIN" FT /evidence="ECO:0000269|PubMed:31215115" FT CARBOHYD 94 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 304..314 FT /evidence="ECO:0000269|PubMed:26919518, FT ECO:0000269|PubMed:28257634, ECO:0007744|PDB:5E4G, FT ECO:0007744|PDB:5JHW, ECO:0007744|PDB:5UHM" FT DISULFID 313..372 FT /evidence="ECO:0000269|PubMed:26919518, FT ECO:0000269|PubMed:28257634, ECO:0007744|PDB:5E4G, FT ECO:0007744|PDB:5JHW, ECO:0007744|PDB:5UHM" FT DISULFID 341..404 FT /evidence="ECO:0000269|PubMed:26919518, FT ECO:0000269|PubMed:28257634, ECO:0007744|PDB:5E4G, FT ECO:0007744|PDB:5JHW, ECO:0007744|PDB:5UHM" FT DISULFID 345..406 FT /evidence="ECO:0000269|PubMed:26919518, FT ECO:0000269|PubMed:28257634, ECO:0007744|PDB:5E4G, FT ECO:0007744|PDB:5JHW, ECO:0007744|PDB:5UHM" FT DISULFID 371 FT /note="Interchain" FT /evidence="ECO:0000269|PubMed:26919518, FT ECO:0000269|PubMed:28257634, ECO:0007744|PDB:5E4G, FT ECO:0007744|PDB:5JHW, ECO:0007744|PDB:5UHM" FT VARIANT 298 FT /note="R -> Q (in VHO; loss of proteolytic cleavage of FT N-terminal propeptide; markedly reduced function in the FT activation of SMAD protein signal transduction; FT dbSNP:rs1878258280)" FT /evidence="ECO:0000269|PubMed:31215115" FT /id="VAR_085163" FT STRAND 301..304 FT /evidence="ECO:0007829|PDB:5UHM" FT STRAND 306..308 FT /evidence="ECO:0007829|PDB:7MRZ" FT STRAND 312..316 FT /evidence="ECO:0007829|PDB:5E4G" FT STRAND 319..321 FT /evidence="ECO:0007829|PDB:5E4G" FT TURN 322..326 FT /evidence="ECO:0007829|PDB:5E4G" FT STRAND 330..332 FT /evidence="ECO:0007829|PDB:5E4G" FT STRAND 334..337 FT /evidence="ECO:0007829|PDB:5E4G" FT STRAND 340..342 FT /evidence="ECO:0007829|PDB:5E4G" FT TURN 347..350 FT /evidence="ECO:0007829|PDB:5E4G" FT HELIX 355..362 FT /evidence="ECO:0007829|PDB:5E4G" FT STRAND 365..367 FT /evidence="ECO:0007829|PDB:6MAC" FT STRAND 371..385 FT /evidence="ECO:0007829|PDB:5E4G" FT STRAND 387..389 FT /evidence="ECO:0007829|PDB:5E4G" FT STRAND 391..407 FT /evidence="ECO:0007829|PDB:5E4G" SQ SEQUENCE 407 AA; 45091 MW; E8FF48E363635BA8 CRC64; MVLAAPLLLG FLLLALELRP RGEAAEGPAA AAAAAAAAAA AGVGGERSSR PAPSVAPEPD GCPVCVWRQH SRELRLESIK SQILSKLRLK EAPNISREVV KQLLPKAPPL QQILDLHDFQ GDALQPEDFL EEDEYHATTE TVISMAQETD PAVQTDGSPL CCHFHFSPKV MFTKVLKAQL WVYLRPVPRP ATVYLQILRL KPLTGEGTAG GGGGGRRHIR IRSLKIELHS RSGHWQSIDF KQVLHSWFRQ PQSNWGIEIN AFDPSGTDLA VTSLGPGAEG LHPFMELRVL ENTKRSRRNL GLDCDEHSSE SRCCRYPLTV DFEAFGWDWI IAPKRYKANY CSGQCEYMFM QKYPHTHLVQ QANPRGSAGP CCTPTKMSPI NMLYFNDKQQ IIYGKIPGMV VDRCGCS //