GDF11_HUMAN
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 03-AUG-2022, entry version 168.
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 and
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}.
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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 GlyGen; O95390; 1 site.
DR iPTMnet; O95390; -.
DR PhosphoSitePlus; O95390; -.
DR BioMuta; GDF11; -.
DR MassIVE; O95390; -.
DR PaxDb; O95390; -.
DR PeptideAtlas; O95390; -.
DR PRIDE; O95390; -.
DR ProteomicsDB; 50842; -.
DR Antibodypedia; 27725; 287 antibodies from 33 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 CTD; 10220; -.
DR DisGeNET; 10220; -.
DR GeneCards; GDF11; -.
DR HGNC; HGNC:4216; GDF11.
DR HPA; ENSG00000135414; Tissue enhanced (brain, 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; NSRAGHW; -.
DR OrthoDB; 892873at2759; -.
DR PhylomeDB; O95390; -.
DR TreeFam; TF318514; -.
DR PathwayCommons; O95390; -.
DR SignaLink; O95390; -.
DR SIGNOR; O95390; -.
DR BioGRID-ORCS; 10220; 17 hits in 1085 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 169 other tissues.
DR ExpressionAtlas; O95390; baseline and differential.
DR Genevisible; O95390; HS.
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:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IBA:GO_Central.
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 Gene3D; 2.10.90.10; -; 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; PTHR11848; 1.
DR Pfam; PF00019; TGF_beta; 1.
DR Pfam; PF00688; TGFb_propeptide; 1.
DR SMART; SM00204; TGFB; 1.
DR SUPFAM; SSF57501; SSF57501; 1.
DR PROSITE; PS00250; TGF_BETA_1; 1.
DR PROSITE; PS51362; TGF_BETA_2; 1.
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 N-
FT terminal propeptide; markedly reduced function in the
FT activation of SMAD protein signal transduction)"
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
