GDF8_HUMAN
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 03-AUG-2022, entry version 185.
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_0000033951; PRO_0000033950 [O14793]: MSTN; NbExp=3; IntAct=EBI-20717179, EBI-20717185;
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";
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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; MYO-029.
DR DrugCentral; O14793; -.
DR GlyGen; O14793; 1 site.
DR iPTMnet; O14793; -.
DR PhosphoSitePlus; O14793; -.
DR BioMuta; MSTN; -.
DR MassIVE; O14793; -.
DR PaxDb; O14793; -.
DR PeptideAtlas; O14793; -.
DR PRIDE; O14793; -.
DR ProteomicsDB; 48243; -.
DR ABCD; O14793; 26 sequenced antibodies.
DR Antibodypedia; 4098; 729 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 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 Orphanet; 275534; Myostatin-related muscle hypertrophy.
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; QICVYIY; -.
DR OrthoDB; 892873at2759; -.
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; 7 hits in 1066 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 vastus lateralis and 94 other tissues.
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: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-UCL.
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; 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
