ID GDF8_HUMAN Reviewed; 375 AA. AC O14793; A1C2J7; A1C2K0; Q6B0H2; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 27-MAR-2024, entry version 194. DE RecName: Full=Growth/differentiation factor 8; DE Short=GDF-8; DE AltName: Full=Myostatin; DE Flags: Precursor; GN Name=MSTN; Synonyms=GDF8; 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=Skeletal muscle; RX PubMed=9356471; DOI=10.1073/pnas.94.23.12457; RA McPherron A.C., Lee S.-J.; RT "Double muscling in cattle due to mutations in the myostatin gene."; RL Proc. Natl. Acad. Sci. U.S.A. 94:12457-12461(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Muscle; RX PubMed=9843994; DOI=10.1073/pnas.95.25.14938; RA Gonzalez-Cadavid N.F., Taylor W.E., Yarasheski K., Sinha-Hikim I., Ma K., RA Ezzat S., Shen R., Lalani R., Asa S., Mamita M., Nair G., Arver S., RA Bhasin S.; RT "Organization of the human myostatin gene and expression in healthy men and RT HIV-infected men with muscle wasting."; RL Proc. Natl. Acad. Sci. U.S.A. 95:14938-14943(1998). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-55 AND ARG-153. RX PubMed=17186467; DOI=10.1086/509707; RA Saunders M.A., Good J.M., Lawrence E.C., Ferrell R.E., Li W.H., RA Nachman M.W.; RT "Human adaptive evolution at myostatin (GDF8), a regulator of muscle RT growth."; RL Am. J. Hum. Genet. 79:1089-1097(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Colon; 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 [5] RP INTERACTION WITH WFIKKN2. RX PubMed=12595574; DOI=10.1210/me.2002-0366; RA Hill J.J., Qiu Y., Hewick R.M., Wolfman N.M.; RT "Regulation of myostatin in vivo by growth and differentiation factor- RT associated serum protein-1: a novel protein with protease inhibitor and RT follistatin domains."; RL Mol. Endocrinol. 17:1144-1154(2003). RN [6] RP INVOLVEMENT IN MSLHP. RX PubMed=15215484; DOI=10.1056/nejmoa040933; RA Schuelke M., Wagner K.R., Stolz L.E., Hubner C., Riebel T., Komen W., RA Braun T., Tobin J.F., Lee S.J.; RT "Myostatin mutation associated with gross muscle hypertrophy in a child."; RL N. Engl. J. Med. 350:2682-2688(2004). RN [7] RP INTERACTION WITH FSTL3. RX PubMed=17878677; DOI=10.2152/jmi.54.276; RA Takehara-Kasamatsu Y., Tsuchida K., Nakatani M., Murakami T., Kurisaki A., RA Hashimoto O., Ohuchi H., Kurose H., Mori K., Kagami S., Noji S., Sugino H.; RT "Characterization of follistatin-related gene as a negative regulatory RT factor for activin family members during mouse heart development."; RL J. Med. Invest. 54:276-288(2007). RN [8] {ECO:0007744|PDB:5F3B, ECO:0007744|PDB:5F3H} RP X-RAY CRYSTALLOGRAPHY (1.76 ANGSTROMS) OF 267-375 IN COMPLEX WITH ANTI-MSTN RP ANTIBODY, DISULFIDE BONDS, AND SUBUNIT. RX PubMed=27625211; DOI=10.1080/19420862.2016.1215786; RA Apgar J.R., Mader M., Agostinelli R., Benard S., Bialek P., Johnson M., RA Gao Y., Krebs M., Owens J., Parris K., St Andre M., Svenson K., Morris C., RA Tchistiakova L.; RT "Beyond CDR-grafting: Structure-guided humanization of framework and CDR RT regions of an anti-myostatin antibody."; RL MAbs 8:1302-1318(2016). RN [9] RP MUTAGENESIS OF ASP-267; PHE-268; GLU-312; PHE-315; VAL-316; LEU-318; RP HIS-328; GLY-355; GLU-357 AND ALA-366. 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: Acts specifically as a negative regulator of skeletal muscle CC growth. {ECO:0000250|UniProtKB:O08689}. CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:27625211). Interacts with CC WFIKKN2, leading to inhibit its activity (PubMed:12595574). Interacts CC with FST3 (PubMed:17878677). {ECO:0000269|PubMed:12595574, CC ECO:0000269|PubMed:17878677, ECO:0000269|PubMed:27625211}. CC -!- INTERACTION: CC O14793; Q13705: ACVR2B; NbExp=4; IntAct=EBI-8542977, EBI-1383577; CC O14793; P13497: BMP1; NbExp=2; IntAct=EBI-8542977, EBI-489827; CC O14793; P09958: FURIN; NbExp=2; IntAct=EBI-8542977, EBI-1056807; CC O14793; O14793: MSTN; NbExp=6; IntAct=EBI-8542977, EBI-8542977; CC O14793; Q96NZ8: WFIKKN1; NbExp=4; IntAct=EBI-8542977, EBI-2363713; CC PRO_0000033950; PRO_0000033951 [O14793]: MSTN; NbExp=3; IntAct=EBI-20717185, EBI-20717179; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:O08689}. CC -!- PTM: Synthesized as large precursor molecule that undergoes proteolytic CC cleavage to generate an N-terminal propeptide and a disulfide linked C- CC terminal dimer, which is the biologically active molecule. The CC circulating form consists of a latent complex of the C-terminal dimer CC and other proteins, including its propeptide, which maintain the C- CC terminal dimer in a latent, inactive state. Ligand activation requires CC additional cleavage of the prodomain by a tolloid-like CC metalloproteinase. {ECO:0000250|UniProtKB:O08689}. CC -!- DISEASE: Muscle hypertrophy (MSLHP) [MIM:614160]: A condition CC characterized by increased muscle bulk and strength. Affected CC individuals are exceptionally strong. {ECO:0000269|PubMed:15215484}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Myostatin entry; CC URL="https://en.wikipedia.org/wiki/Myostatin"; 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; AF019627; AAB86694.1; -; mRNA. DR EMBL; AF104922; AAC96327.1; -; mRNA. DR EMBL; DQ927096; ABI48419.1; -; Genomic_DNA. DR EMBL; DQ927098; ABI48421.1; -; Genomic_DNA. DR EMBL; DQ927099; ABI48422.1; -; Genomic_DNA. DR EMBL; BC074757; AAH74757.2; -; mRNA. DR CCDS; CCDS2303.1; -. DR RefSeq; NP_005250.1; NM_005259.2. DR PDB; 5F3B; X-ray; 1.76 A; C/D=267-375. DR PDB; 5F3H; X-ray; 2.70 A; I/J/K/L=268-375. DR PDB; 5NTU; X-ray; 2.58 A; A/B=43-375. DR PDB; 5NXS; X-ray; 4.19 A; A/B=43-375. DR PDB; 6UMX; X-ray; 2.79 A; A/B=24-375. DR PDBsum; 5F3B; -. DR PDBsum; 5F3H; -. DR PDBsum; 5NTU; -. DR PDBsum; 5NXS; -. DR PDBsum; 6UMX; -. DR AlphaFoldDB; O14793; -. DR SMR; O14793; -. DR BioGRID; 108929; 38. DR IntAct; O14793; 4. DR MINT; O14793; -. DR STRING; 9606.ENSP00000260950; -. DR BindingDB; O14793; -. DR ChEMBL; CHEMBL3407325; -. DR DrugBank; DB05915; Stamulumab. DR DrugCentral; O14793; -. DR GlyCosmos; O14793; 1 site, No reported glycans. DR GlyGen; O14793; 1 site. DR iPTMnet; O14793; -. DR PhosphoSitePlus; O14793; -. DR BioMuta; MSTN; -. DR MassIVE; O14793; -. DR PaxDb; 9606-ENSP00000260950; -. DR PeptideAtlas; O14793; -. DR ProteomicsDB; 48243; -. DR ABCD; O14793; 26 sequenced antibodies. DR Antibodypedia; 4098; 994 antibodies from 38 providers. DR DNASU; 2660; -. DR Ensembl; ENST00000260950.5; ENSP00000260950.3; ENSG00000138379.5. DR GeneID; 2660; -. DR KEGG; hsa:2660; -. DR MANE-Select; ENST00000260950.5; ENSP00000260950.3; NM_005259.3; NP_005250.1. DR AGR; HGNC:4223; -. DR CTD; 2660; -. DR DisGeNET; 2660; -. DR GeneCards; MSTN; -. DR HGNC; HGNC:4223; MSTN. DR HPA; ENSG00000138379; Tissue enhanced (skeletal muscle, tongue). DR MalaCards; MSTN; -. DR MIM; 601788; gene. DR MIM; 614160; phenotype. DR neXtProt; NX_O14793; -. DR OpenTargets; ENSG00000138379; -. DR PharmGKB; PA162396253; -. DR VEuPathDB; HostDB:ENSG00000138379; -. DR eggNOG; KOG3900; Eukaryota. DR GeneTree; ENSGT00940000160657; -. DR HOGENOM; CLU_020515_6_1_1; -. DR InParanoid; O14793; -. DR OMA; TDQCATC; -. DR OrthoDB; 3015718at2759; -. DR PhylomeDB; O14793; -. DR TreeFam; TF318514; -. DR PathwayCommons; O14793; -. DR Reactome; R-HSA-9617828; FOXO-mediated transcription of cell cycle genes. DR SignaLink; O14793; -. DR SIGNOR; O14793; -. DR BioGRID-ORCS; 2660; 9 hits in 1144 CRISPR screens. DR GeneWiki; Myostatin; -. DR GenomeRNAi; 2660; -. DR Pharos; O14793; Tclin. DR PRO; PR:O14793; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; O14793; Protein. DR Bgee; ENSG00000138379; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 94 other cell types or tissues. DR ExpressionAtlas; O14793; baseline and differential. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central. DR GO; GO:0008083; F:growth factor activity; TAS:ProtInc. DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW. DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IEA:Ensembl. DR GO; GO:0005102; F:signaling receptor binding; IPI:BHF-UCL. DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEA:Ensembl. DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl. DR GO; GO:0046716; P:muscle cell cellular homeostasis; IDA:CACAO. DR GO; GO:0007517; P:muscle organ development; TAS:ProtInc. DR GO; GO:0014839; P:myoblast migration involved in skeletal muscle regeneration; ISS:UniProtKB. DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IEA:Ensembl. DR GO; GO:0014741; P:negative regulation of muscle hypertrophy; IEA:Ensembl. DR GO; GO:0045662; P:negative regulation of myoblast differentiation; IDA:CACAO. DR GO; GO:2000818; P:negative regulation of myoblast proliferation; ISS:AgBase. DR GO; GO:0051898; P:negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:CACAO. DR GO; GO:1902725; P:negative regulation of satellite cell differentiation; ISS:AgBase. DR GO; GO:1902723; P:negative regulation of skeletal muscle satellite cell proliferation; ISS:AgBase. DR GO; GO:0048632; P:negative regulation of skeletal muscle tissue growth; IMP:CACAO. DR GO; GO:0022602; P:ovulation cycle process; IEA:Ensembl. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:HGNC-UCL. DR GO; GO:0010592; P:positive regulation of lamellipodium assembly; ISS:UniProtKB. DR GO; GO:0010759; P:positive regulation of macrophage chemotaxis; ISS:UniProtKB. DR GO; GO:0051602; P:response to electrical stimulus; IEA:Ensembl. DR GO; GO:0043627; P:response to estrogen; IEA:Ensembl. DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl. DR GO; GO:0009629; P:response to gravity; IEA:Ensembl. DR GO; GO:0014850; P:response to muscle activity; IEA:Ensembl. DR GO; GO:0033574; P:response to testosterone; IEA:Ensembl. DR GO; GO:0014732; P:skeletal muscle atrophy; IEA:Ensembl. DR GO; GO:0014816; P:skeletal muscle satellite cell differentiation; IEA:Ensembl. DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; 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:SF150; GROWTH_DIFFERENTIATION FACTOR 8; 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; O14793; HS. PE 1: Evidence at protein level; KW 3D-structure; Cleavage on pair of basic residues; Cytokine; Disulfide bond; KW Glycoprotein; Growth factor; Heparin-binding; Reference proteome; Secreted; KW Signal. FT SIGNAL 1..23 FT /evidence="ECO:0000255" FT PROPEP 24..266 FT /evidence="ECO:0000255" FT /id="PRO_0000033950" FT CHAIN 267..375 FT /note="Growth/differentiation factor 8" FT /id="PRO_0000033951" FT SITE 98..99 FT /note="Cleavage" FT /evidence="ECO:0000250|UniProtKB:O08689" FT CARBOHYD 71 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 272..282 FT /evidence="ECO:0000269|PubMed:27625211, FT ECO:0007744|PDB:5F3B, ECO:0007744|PDB:5F3H" FT DISULFID 281..340 FT /evidence="ECO:0000269|PubMed:27625211, FT ECO:0007744|PDB:5F3B, ECO:0007744|PDB:5F3H" FT DISULFID 309..372 FT /evidence="ECO:0000269|PubMed:27625211, FT ECO:0007744|PDB:5F3B, ECO:0007744|PDB:5F3H" FT DISULFID 313..374 FT /evidence="ECO:0000269|PubMed:27625211, FT ECO:0007744|PDB:5F3B, ECO:0007744|PDB:5F3H" FT DISULFID 339 FT /note="Interchain" FT /evidence="ECO:0000269|PubMed:27625211, FT ECO:0007744|PDB:5F3B, ECO:0007744|PDB:5F3H" FT VARIANT 55 FT /note="A -> T (in dbSNP:rs1805085)" FT /evidence="ECO:0000269|PubMed:17186467" FT /id="VAR_014475" FT VARIANT 153 FT /note="K -> R (in dbSNP:rs1805086)" FT /evidence="ECO:0000269|PubMed:17186467" FT /id="VAR_014476" FT VARIANT 348 FT /note="I -> T (in dbSNP:rs34780010)" FT /id="VAR_052575" FT VARIANT 371 FT /note="R -> G (in dbSNP:rs16823988)" FT /id="VAR_052576" FT MUTAGEN 267 FT /note="D->N: Decreases SMAD3 protein signal transduction; FT when associated with L-268." FT /evidence="ECO:0000269|PubMed:28257634" FT MUTAGEN 268 FT /note="F->L: Decreases SMAD3 protein signal transduction; FT when associated with N-267." FT /evidence="ECO:0000269|PubMed:28257634" FT MUTAGEN 312 FT /note="E->Q: Slightly decreased SMAD3 protein signal FT transduction." FT /evidence="ECO:0000269|PubMed:28257634" FT MUTAGEN 315 FT /note="F->Y: Increases SMAD3 protein signal transduction; FT when associated with M-316 and M-318." FT /evidence="ECO:0000269|PubMed:28257634" FT MUTAGEN 316 FT /note="V->M: Increases SMAD3 protein signal transduction; FT when associated with Y-315 and M-318." FT /evidence="ECO:0000269|PubMed:28257634" FT MUTAGEN 318 FT /note="L->M: Increases SMAD3 protein signal transduction; FT when associated with Y-315 and M-316." FT /evidence="ECO:0000269|PubMed:28257634" FT MUTAGEN 328 FT /note="H->Q: Increases SMAD3 protein signal transduction." FT /evidence="ECO:0000269|PubMed:28257634" FT MUTAGEN 355 FT /note="G->D: Increases SMAD3 protein signal transduction; FT when associated with Q-357." FT /evidence="ECO:0000269|PubMed:28257634" FT MUTAGEN 357 FT /note="E->Q: Increases SMAD3 protein signal transduction; FT when associated with D-355." FT /evidence="ECO:0000269|PubMed:28257634" FT MUTAGEN 366 FT /note="A->G: Increases SMAD3 protein signal transduction." FT /evidence="ECO:0000269|PubMed:28257634" FT HELIX 47..63 FT /evidence="ECO:0007829|PDB:5NTU" FT HELIX 74..80 FT /evidence="ECO:0007829|PDB:5NTU" FT HELIX 85..92 FT /evidence="ECO:0007829|PDB:5NTU" FT STRAND 110..112 FT /evidence="ECO:0007829|PDB:6UMX" FT STRAND 114..120 FT /evidence="ECO:0007829|PDB:5NTU" FT HELIX 148..150 FT /evidence="ECO:0007829|PDB:5NTU" FT STRAND 151..160 FT /evidence="ECO:0007829|PDB:5NTU" FT STRAND 167..176 FT /evidence="ECO:0007829|PDB:5NTU" FT STRAND 181..183 FT /evidence="ECO:0007829|PDB:6UMX" FT STRAND 185..196 FT /evidence="ECO:0007829|PDB:5NTU" FT STRAND 202..207 FT /evidence="ECO:0007829|PDB:5NTU" FT HELIX 209..216 FT /evidence="ECO:0007829|PDB:5NTU" FT TURN 217..219 FT /evidence="ECO:0007829|PDB:5NTU" FT STRAND 223..230 FT /evidence="ECO:0007829|PDB:5NTU" FT STRAND 243..245 FT /evidence="ECO:0007829|PDB:6UMX" FT STRAND 252..257 FT /evidence="ECO:0007829|PDB:5NTU" FT STRAND 280..284 FT /evidence="ECO:0007829|PDB:5F3B" FT STRAND 287..289 FT /evidence="ECO:0007829|PDB:5F3B" FT HELIX 290..293 FT /evidence="ECO:0007829|PDB:5F3B" FT STRAND 298..300 FT /evidence="ECO:0007829|PDB:5F3B" FT STRAND 302..305 FT /evidence="ECO:0007829|PDB:5F3B" FT STRAND 308..310 FT /evidence="ECO:0007829|PDB:5F3B" FT HELIX 318..320 FT /evidence="ECO:0007829|PDB:5F3B" FT HELIX 321..330 FT /evidence="ECO:0007829|PDB:5F3B" FT STRAND 335..337 FT /evidence="ECO:0007829|PDB:5F3B" FT STRAND 340..353 FT /evidence="ECO:0007829|PDB:5F3B" FT STRAND 359..374 FT /evidence="ECO:0007829|PDB:5F3B" SQ SEQUENCE 375 AA; 42750 MW; EBFF6129725E6AFA CRC64; MQKLQLCVYI YLFMLIVAGP VDLNENSEQK ENVEKEGLCN ACTWRQNTKS SRIEAIKIQI LSKLRLETAP NISKDVIRQL LPKAPPLREL IDQYDVQRDD SSDGSLEDDD YHATTETIIT MPTESDFLMQ VDGKPKCCFF KFSSKIQYNK VVKAQLWIYL RPVETPTTVF VQILRLIKPM KDGTRYTGIR SLKLDMNPGT GIWQSIDVKT VLQNWLKQPE SNLGIEIKAL DENGHDLAVT FPGPGEDGLN PFLEVKVTDT PKRSRRDFGL DCDEHSTESR CCRYPLTVDF EAFGWDWIIA PKRYKANYCS GECEFVFLQK YPHTHLVHQA NPRGSAGPCC TPTKMSPINM LYFNGKEQII YGKIPAMVVD RCGCS //