ID   GDF8_MOUSE              Reviewed;         376 AA.
AC   O08689;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-JUL-1997, sequence version 1.
DT   27-MAR-2024, entry version 172.
DE   RecName: Full=Growth/differentiation factor 8;
DE            Short=GDF-8;
DE   AltName: Full=Myostatin;
DE   Flags: Precursor;
GN   Name=Mstn; Synonyms=Gdf8;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, DEVELOPMENTAL STAGE, AND TISSUE
RP   SPECIFICITY.
RC   STRAIN=CD-1; TISSUE=Skeletal muscle;
RX   PubMed=9139826; DOI=10.1038/387083a0;
RA   McPherron A.C., Lawler A.M., Lee S.-J.;
RT   "Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily
RT   member.";
RL   Nature 387:83-90(1997).
RN   [2]
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   [3]
RP   PROTEOLYTIC CLEAVAGE AT ARG-99, MUTAGENESIS OF ARG-99 AND ASP-100,
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=14671324; DOI=10.1073/pnas.2534946100;
RA   Wolfman N.M., McPherron A.C., Pappano W.N., Davies M.V., Song K.,
RA   Tomkinson K.N., Wright J.F., Zhao L., Sebald S.M., Greenspan D.S.,
RA   Lee S.J.;
RT   "Activation of latent myostatin by the BMP-1/tolloid family of
RT   metalloproteinases.";
RL   Proc. Natl. Acad. Sci. U.S.A. 100:15842-15846(2003).
RN   [4]
RP   DISRUPTION PHENOTYPE, AND FUNCTION.
RX   PubMed=24076600; DOI=10.1038/ng.2772;
RA   Sartori R., Schirwis E., Blaauw B., Bortolanza S., Zhao J., Enzo E.,
RA   Stantzou A., Mouisel E., Toniolo L., Ferry A., Stricker S., Goldberg A.L.,
RA   Dupont S., Piccolo S., Amthor H., Sandri M.;
RT   "BMP signaling controls muscle mass.";
RL   Nat. Genet. 45:1309-1318(2013).
RN   [5]
RP   X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 268-376 IN COMPLEX WITH HUMAN
RP   FST, SUBUNIT, HEPARIN-BINDING, AND DISULFIDE BONDS.
RX   PubMed=19644449; DOI=10.1038/emboj.2009.205;
RA   Cash J.N., Rejon C.A., McPherron A.C., Bernard D.J., Thompson T.B.;
RT   "The structure of myostatin:follistatin 288: insights into receptor
RT   utilization and heparin binding.";
RL   EMBO J. 28:2662-2676(2009).
RN   [6]
RP   X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 268-376 IN COMPLEX WITH HUMAN
RP   FSTL3, AND DISULFIDE BONDS.
RX   PubMed=22052913; DOI=10.1074/jbc.m111.270801;
RA   Cash J.N., Angerman E.B., Kattamuri C., Nolan K., Zhao H., Sidis Y.,
RA   Keutmann H.T., Thompson T.B.;
RT   "Structure of myostatin.follistatin-like 3: N-terminal domains of
RT   follistatin-type molecules exhibit alternate modes of binding.";
RL   J. Biol. Chem. 287:1043-1053(2012).
CC   -!- FUNCTION: Acts specifically as a negative regulator of skeletal muscle
CC       growth. {ECO:0000269|PubMed:14671324, ECO:0000269|PubMed:24076600,
CC       ECO:0000269|PubMed:9139826}.
CC   -!- SUBUNIT: Homodimer; disulfide-linked (PubMed:19644449). Interacts with
CC       WFIKKN2, leading to inhibit its activity (PubMed:12595574). Interacts
CC       with FSTL3 (PubMed:22052913). {ECO:0000269|PubMed:12595574,
CC       ECO:0000269|PubMed:19644449, ECO:0000269|PubMed:22052913}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:14671324}.
CC   -!- TISSUE SPECIFICITY: Expressed specifically in developing and adult
CC       skeletal muscle. Weak expression in adipose tissue.
CC       {ECO:0000269|PubMed:9139826}.
CC   -!- DEVELOPMENTAL STAGE: First detected 9.5 dpc in one-third of developing
CC       somites. At 10.5 dpc, expressed in the myotome compartment of somites.
CC       At later stages of development, detected in a wide range of developing
CC       muscles. Expression continues in adulthood.
CC       {ECO:0000269|PubMed:9139826}.
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 (PubMed:14671324). {ECO:0000269|PubMed:14671324}.
CC   -!- DISRUPTION PHENOTYPE: Mutant animals exhibit muscle hypertrophy.
CC       {ECO:0000269|PubMed:24076600}.
CC   -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}.
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DR   EMBL; U84005; AAC53167.1; -; mRNA.
DR   CCDS; CCDS14950.1; -.
DR   RefSeq; NP_034964.1; NM_010834.3.
DR   PDB; 3HH2; X-ray; 2.15 A; A/B=268-376.
DR   PDB; 3SEK; X-ray; 2.40 A; B=268-376.
DR   PDB; 5JI1; X-ray; 2.25 A; A/B=268-376.
DR   PDBsum; 3HH2; -.
DR   PDBsum; 3SEK; -.
DR   PDBsum; 5JI1; -.
DR   AlphaFoldDB; O08689; -.
DR   SMR; O08689; -.
DR   BioGRID; 201535; 1.
DR   IntAct; O08689; 4.
DR   MINT; O08689; -.
DR   STRING; 10090.ENSMUSP00000027269; -.
DR   BindingDB; O08689; -.
DR   ChEMBL; CHEMBL3588736; -.
DR   GlyCosmos; O08689; 1 site, No reported glycans.
DR   GlyGen; O08689; 1 site.
DR   iPTMnet; O08689; -.
DR   PhosphoSitePlus; O08689; -.
DR   CPTAC; non-CPTAC-3298; -.
DR   PaxDb; 10090-ENSMUSP00000027269; -.
DR   PeptideAtlas; O08689; -.
DR   ProteomicsDB; 273042; -.
DR   ABCD; O08689; 5 sequenced antibodies.
DR   Antibodypedia; 4098; 994 antibodies from 38 providers.
DR   DNASU; 17700; -.
DR   Ensembl; ENSMUST00000027269.7; ENSMUSP00000027269.6; ENSMUSG00000026100.7.
DR   GeneID; 17700; -.
DR   KEGG; mmu:17700; -.
DR   UCSC; uc007ayt.1; mouse.
DR   AGR; MGI:95691; -.
DR   CTD; 2660; -.
DR   MGI; MGI:95691; Mstn.
DR   VEuPathDB; HostDB:ENSMUSG00000026100; -.
DR   eggNOG; KOG3900; Eukaryota.
DR   GeneTree; ENSGT00940000160657; -.
DR   HOGENOM; CLU_020515_6_1_1; -.
DR   InParanoid; O08689; -.
DR   OMA; TDQCATC; -.
DR   OrthoDB; 3015718at2759; -.
DR   PhylomeDB; O08689; -.
DR   TreeFam; TF318514; -.
DR   BioGRID-ORCS; 17700; 2 hits in 76 CRISPR screens.
DR   EvolutionaryTrace; O08689; -.
DR   PRO; PR:O08689; -.
DR   Proteomes; UP000000589; Chromosome 1.
DR   RNAct; O08689; Protein.
DR   Bgee; ENSMUSG00000026100; Expressed in gastrocnemius and 44 other cell types or tissues.
DR   ExpressionAtlas; O08689; baseline and differential.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
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; IEA:UniProtKB-KW.
DR   GO; GO:0008201; F:heparin binding; IDA:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0005102; F:signaling receptor binding; IPI:MGI.
DR   GO; GO:0071549; P:cellular response to dexamethasone stimulus; IDA:MGI.
DR   GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR   GO; GO:0046716; P:muscle cell cellular homeostasis; ISO:MGI.
DR   GO; GO:0014839; P:myoblast migration involved in skeletal muscle regeneration; IMP:UniProtKB.
DR   GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; IMP:CACAO.
DR   GO; GO:0033673; P:negative regulation of kinase activity; IMP:CACAO.
DR   GO; GO:0014741; P:negative regulation of muscle hypertrophy; ISO:MGI.
DR   GO; GO:0045662; P:negative regulation of myoblast differentiation; ISO:MGI.
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; ISO:MGI.
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:UniProtKB.
DR   GO; GO:0022602; P:ovulation cycle process; IEA:Ensembl.
DR   GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISO:MGI.
DR   GO; GO:0010592; P:positive regulation of lamellipodium assembly; IMP:UniProtKB.
DR   GO; GO:0010759; P:positive regulation of macrophage chemotaxis; IMP: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; IMP:MGI.
DR   GO; GO:0043403; P:skeletal muscle tissue regeneration; IMP:MGI.
DR   GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:MGI.
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   IDEAL; IID50111; -.
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.
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..24
FT                   /evidence="ECO:0000255"
FT   PROPEP          25..267
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000033956"
FT   CHAIN           268..376
FT                   /note="Growth/differentiation factor 8"
FT                   /id="PRO_0000033957"
FT   SITE            99..100
FT                   /note="Cleavage"
FT                   /evidence="ECO:0000269|PubMed:14671324"
FT   CARBOHYD        72
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        273..283
FT                   /evidence="ECO:0000269|PubMed:19644449,
FT                   ECO:0000269|PubMed:22052913, ECO:0007744|PDB:3HH2,
FT                   ECO:0007744|PDB:3SEK"
FT   DISULFID        282..341
FT                   /evidence="ECO:0000269|PubMed:19644449,
FT                   ECO:0000269|PubMed:22052913, ECO:0007744|PDB:3HH2,
FT                   ECO:0007744|PDB:3SEK"
FT   DISULFID        310..373
FT                   /evidence="ECO:0000269|PubMed:19644449,
FT                   ECO:0000269|PubMed:22052913, ECO:0007744|PDB:3HH2,
FT                   ECO:0007744|PDB:3SEK"
FT   DISULFID        314..375
FT                   /evidence="ECO:0000269|PubMed:19644449,
FT                   ECO:0000269|PubMed:22052913, ECO:0007744|PDB:3HH2,
FT                   ECO:0007744|PDB:3SEK"
FT   DISULFID        340
FT                   /note="Interchain"
FT                   /evidence="ECO:0000269|PubMed:19644449,
FT                   ECO:0007744|PDB:3HH2"
FT   MUTAGEN         99
FT                   /note="R->Q: No effect on proteolytic cleavage."
FT                   /evidence="ECO:0000269|PubMed:14671324"
FT   MUTAGEN         100
FT                   /note="D->A: Blocks proteolytic cleavage; increases muscle
FT                   mass when injected into adult mice."
FT                   /evidence="ECO:0000269|PubMed:14671324"
FT   STRAND          281..285
FT                   /evidence="ECO:0007829|PDB:3HH2"
FT   STRAND          288..290
FT                   /evidence="ECO:0007829|PDB:3HH2"
FT   HELIX           291..294
FT                   /evidence="ECO:0007829|PDB:3HH2"
FT   STRAND          299..301
FT                   /evidence="ECO:0007829|PDB:3HH2"
FT   STRAND          303..306
FT                   /evidence="ECO:0007829|PDB:3HH2"
FT   STRAND          309..311
FT                   /evidence="ECO:0007829|PDB:3HH2"
FT   TURN            316..319
FT                   /evidence="ECO:0007829|PDB:3HH2"
FT   HELIX           324..331
FT                   /evidence="ECO:0007829|PDB:3HH2"
FT   STRAND          340..354
FT                   /evidence="ECO:0007829|PDB:3HH2"
FT   STRAND          356..358
FT                   /evidence="ECO:0007829|PDB:5JI1"
FT   STRAND          360..376
FT                   /evidence="ECO:0007829|PDB:3HH2"
SQ   SEQUENCE   376 AA;  42921 MW;  3E19814DD62C08BE CRC64;
     MMQKLQMYVY IYLFMLIAAG PVDLNEGSER EENVEKEGLC NACAWRQNTR YSRIEAIKIQ
     ILSKLRLETA PNISKDAIRQ LLPRAPPLRE LIDQYDVQRD DSSDGSLEDD DYHATTETII
     TMPTESDFLM QADGKPKCCF FKFSSKIQYN KVVKAQLWIY LRPVKTPTTV FVQILRLIKP
     MKDGTRYTGI RSLKLDMSPG TGIWQSIDVK TVLQNWLKQP ESNLGIEIKA LDENGHDLAV
     TFPGPGEDGL NPFLEVKVTD TPKRSRRDFG LDCDEHSTES RCCRYPLTVD FEAFGWDWII
     APKRYKANYC SGECEFVFLQ KYPHTHLVHQ ANPRGSAGPC CTPTKMSPIN MLYFNGKEQI
     IYGKIPAMVV DRCGCS
//