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 13-FEB-2019, entry version 166. 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; 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., RA Ma K., Ezzat S., Shen R., Lalani R., Asa S., Mamita M., Nair G., RA Arver S., Bhasin S.; RT "Organization of the human myostatin gene and expression in healthy RT men and 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 RT project: 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 RT and 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 RT 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., RA Kurisaki A., Hashimoto O., Ohuchi H., Kurose H., Mori K., Kagami S., RA 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:0000244|PDB:5F3B, ECO:0000244|PDB:5F3H} RP X-RAY CRYSTALLOGRAPHY (1.76 ANGSTROMS) OF 267-375 IN COMPLEX WITH RP ANTI-MSTN 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., RA Johnson M., Gao Y., Krebs M., Owens J., Parris K., St Andre M., RA Svenson K., Morris C., Tchistiakova L.; RT "Beyond CDR-grafting: Structure-guided humanization of framework and RT CDR 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., RA Oh J., Aykul S., Walton K.L., Schang G., Bernard D.J., Hinck A.P., RA Harrison C.A., Martinez-Hackert E., Wagers A.J., Lee R.T., RA 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 CC muscle growth. {ECO:0000250|UniProtKB:O08689}. CC -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:27625211). Interacts CC with WFIKKN2, leading to inhibit its activity (PubMed:12595574). CC Interacts with FST3 (PubMed:17878677). CC {ECO:0000269|PubMed:12595574, ECO:0000269|PubMed:17878677, CC ECO:0000269|PubMed:27625211}. CC -!- INTERACTION: CC Self; NbExp=6; IntAct=EBI-8542977, EBI-8542977; CC Q13705:ACVR2B; NbExp=4; IntAct=EBI-8542977, EBI-1383577; CC P13497:BMP1; NbExp=2; IntAct=EBI-8542977, EBI-489827; CC P09958:FURIN; NbExp=2; IntAct=EBI-8542977, EBI-1056807; CC Q96NZ8:WFIKKN1; NbExp=4; IntAct=EBI-8542977, EBI-2363713; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:O08689}. CC -!- PTM: Synthesized as large precursor molecule that undergoes CC proteolytic cleavage to generate an N-terminal propeptide and a CC disulfide linked C-terminal dimer, which is the biologically CC active molecule. The circulating form consists of a latent complex CC of the C-terminal dimer and other proteins, including its CC propeptide, which maintain the C-terminal dimer in a latent, CC inactive state. Ligand activation requires additional cleavage of CC the prodomain by a tolloid-like metalloproteinase. CC {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. CC {ECO:0000269|PubMed:15215484}. Note=The disease is caused by CC mutations affecting the gene represented 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 UniGene; Hs.41565; -. 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 PDBsum; 5F3B; -. DR PDBsum; 5F3H; -. DR PDBsum; 5NTU; -. DR PDBsum; 5NXS; -. DR ProteinModelPortal; O14793; -. DR SMR; O14793; -. DR BioGrid; 108929; 3. DR IntAct; O14793; 4. DR MINT; O14793; -. DR STRING; 9606.ENSP00000260950; -. DR BindingDB; O14793; -. DR ChEMBL; CHEMBL3407325; -. DR DrugBank; DB05915; MYO-029. DR iPTMnet; O14793; -. DR PhosphoSitePlus; O14793; -. DR BioMuta; MSTN; -. DR PaxDb; O14793; -. DR PeptideAtlas; O14793; -. DR PRIDE; O14793; -. DR ProteomicsDB; 48243; -. DR DNASU; 2660; -. DR Ensembl; ENST00000260950; ENSP00000260950; ENSG00000138379. DR GeneID; 2660; -. DR KEGG; hsa:2660; -. DR CTD; 2660; -. DR DisGeNET; 2660; -. DR EuPathDB; HostDB:ENSG00000138379.4; -. DR GeneCards; MSTN; -. DR GeneReviews; MSTN; -. DR HGNC; HGNC:4223; MSTN. DR HPA; CAB009963; -. DR MalaCards; MSTN; -. DR MIM; 601788; gene. DR MIM; 614160; phenotype. DR neXtProt; NX_O14793; -. DR OpenTargets; ENSG00000138379; -. DR Orphanet; 275534; Myostatin-related muscle hypertrophy. DR PharmGKB; PA162396253; -. DR eggNOG; KOG3900; Eukaryota. DR eggNOG; ENOG410XT8Z; LUCA. DR GeneTree; ENSGT00940000160657; -. DR HOGENOM; HOG000006566; -. DR HOVERGEN; HBG000217; -. DR InParanoid; O14793; -. DR KO; K05497; -. DR OMA; NTKYSRI; -. DR OrthoDB; 892873at2759; -. DR PhylomeDB; O14793; -. DR TreeFam; TF318514; -. DR Reactome; R-HSA-9617828; FOXO-mediated transcription of cell cycle genes. DR SIGNOR; O14793; -. DR GeneWiki; Myostatin; -. DR GenomeRNAi; 2660; -. DR PRO; PR:O14793; -. DR Proteomes; UP000005640; Chromosome 2. DR Bgee; ENSG00000138379; Expressed in 98 organ(s), highest expression level in quadriceps femoris. DR ExpressionAtlas; O14793; baseline and differential. DR Genevisible; O14793; HS. DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl. 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:0005160; F:transforming growth factor beta receptor binding; IBA:GO_Central. DR GO; GO:0048468; P:cell development; IBA:GO_Central. DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; 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:0033673; P:negative regulation of kinase activity; 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 protein kinase B signaling; 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:0010592; P:positive regulation of lamellipodium assembly; ISS:UniProtKB. DR GO; GO:0010759; P:positive regulation of macrophage chemotaxis; ISS:UniProtKB. DR GO; GO:0010862; P:positive regulation of pathway-restricted SMAD protein phosphorylation; IBA:GO_Central. DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:HGNC. DR GO; GO:0042981; P:regulation of apoptotic process; IBA:GO_Central. DR GO; GO:0043408; P:regulation of MAPK cascade; IBA:GO_Central. 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:0009408; P:response to heat; 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:0060395; P:SMAD protein signal transduction; IBA:GO_Central. DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IEA:Ensembl. DR Gene3D; 2.10.90.10; -; 1. DR InterPro; IPR029034; Cystine-knot_cytokine. DR InterPro; IPR015616; GDF_8. 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 PANTHER; PTHR11848:SF150; PTHR11848:SF150; 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; Complete proteome; KW Cytokine; Disulfide bond; Glycoprotein; Growth factor; KW Heparin-binding; Polymorphism; Reference proteome; Secreted; Signal. FT SIGNAL 1 23 {ECO:0000255}. FT PROPEP 24 266 {ECO:0000255}. FT /FTId=PRO_0000033950. FT CHAIN 267 375 Growth/differentiation factor 8. FT /FTId=PRO_0000033951. FT SITE 98 99 Cleavage. {ECO:0000250|UniProtKB:O08689}. FT CARBOHYD 71 71 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT DISULFID 272 282 {ECO:0000244|PDB:5F3B, FT ECO:0000244|PDB:5F3H, FT ECO:0000269|PubMed:27625211}. FT DISULFID 281 340 {ECO:0000244|PDB:5F3B, FT ECO:0000244|PDB:5F3H, FT ECO:0000269|PubMed:27625211}. FT DISULFID 309 372 {ECO:0000244|PDB:5F3B, FT ECO:0000244|PDB:5F3H, FT ECO:0000269|PubMed:27625211}. FT DISULFID 313 374 {ECO:0000244|PDB:5F3B, FT ECO:0000244|PDB:5F3H, FT ECO:0000269|PubMed:27625211}. FT DISULFID 339 339 Interchain. {ECO:0000244|PDB:5F3B, FT ECO:0000244|PDB:5F3H, FT ECO:0000269|PubMed:27625211}. FT VARIANT 55 55 A -> T (in dbSNP:rs1805085). FT {ECO:0000269|PubMed:17186467}. FT /FTId=VAR_014475. FT VARIANT 153 153 K -> R (in dbSNP:rs1805086). FT {ECO:0000269|PubMed:17186467}. FT /FTId=VAR_014476. FT VARIANT 348 348 I -> T (in dbSNP:rs34780010). FT /FTId=VAR_052575. FT VARIANT 371 371 R -> G (in dbSNP:rs16823988). FT /FTId=VAR_052576. FT MUTAGEN 267 267 D->N: Decreases SMAD3 protein signal FT transduction; when associated with L-268. FT {ECO:0000269|PubMed:28257634}. FT MUTAGEN 268 268 F->L: Decreases SMAD3 protein signal FT transduction; when associated with N-267. FT {ECO:0000269|PubMed:28257634}. FT MUTAGEN 312 312 E->Q: Slightly decreased SMAD3 protein FT signal transduction. FT {ECO:0000269|PubMed:28257634}. FT MUTAGEN 315 315 F->Y: Increases SMAD3 protein signal FT transduction; when associated with M-316 FT and M-318. {ECO:0000269|PubMed:28257634}. FT MUTAGEN 316 316 V->M: Increases SMAD3 protein signal FT transduction; when associated with Y-315 FT and M-318. {ECO:0000269|PubMed:28257634}. FT MUTAGEN 318 318 L->M: Increases SMAD3 protein signal FT transduction; when associated with Y-315 FT and M-316. {ECO:0000269|PubMed:28257634}. FT MUTAGEN 328 328 H->Q: Increases SMAD3 protein signal FT transduction. FT {ECO:0000269|PubMed:28257634}. FT MUTAGEN 355 355 G->D: Increases SMAD3 protein signal FT transduction; when associated with Q-357. FT {ECO:0000269|PubMed:28257634}. FT MUTAGEN 357 357 E->Q: Increases SMAD3 protein signal FT transduction; when associated with D-355. FT {ECO:0000269|PubMed:28257634}. FT MUTAGEN 366 366 A->G: Increases SMAD3 protein signal FT transduction. FT {ECO:0000269|PubMed:28257634}. FT HELIX 47 63 {ECO:0000244|PDB:5NTU}. FT HELIX 74 80 {ECO:0000244|PDB:5NTU}. FT HELIX 85 92 {ECO:0000244|PDB:5NTU}. FT STRAND 114 120 {ECO:0000244|PDB:5NTU}. FT HELIX 148 150 {ECO:0000244|PDB:5NTU}. FT STRAND 151 160 {ECO:0000244|PDB:5NTU}. FT STRAND 167 176 {ECO:0000244|PDB:5NTU}. FT STRAND 185 196 {ECO:0000244|PDB:5NTU}. FT STRAND 202 207 {ECO:0000244|PDB:5NTU}. FT HELIX 209 216 {ECO:0000244|PDB:5NTU}. FT TURN 217 219 {ECO:0000244|PDB:5NTU}. FT STRAND 223 230 {ECO:0000244|PDB:5NTU}. FT STRAND 252 257 {ECO:0000244|PDB:5NTU}. FT STRAND 280 284 {ECO:0000244|PDB:5F3B}. FT STRAND 287 289 {ECO:0000244|PDB:5F3B}. FT HELIX 290 293 {ECO:0000244|PDB:5F3B}. FT STRAND 298 300 {ECO:0000244|PDB:5F3B}. FT STRAND 302 305 {ECO:0000244|PDB:5F3B}. FT STRAND 308 310 {ECO:0000244|PDB:5F3B}. FT HELIX 318 320 {ECO:0000244|PDB:5F3B}. FT HELIX 321 330 {ECO:0000244|PDB:5F3B}. FT STRAND 335 337 {ECO:0000244|PDB:5F3B}. FT STRAND 340 353 {ECO:0000244|PDB:5F3B}. FT STRAND 359 374 {ECO:0000244|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 //