GDF8_MOUSE
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 03-AUG-2022, entry version 163.
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 GlyGen; O08689; 1 site.
DR iPTMnet; O08689; -.
DR PhosphoSitePlus; O08689; -.
DR CPTAC; non-CPTAC-3298; -.
DR PaxDb; O08689; -.
DR PeptideAtlas; O08689; -.
DR PRIDE; O08689; -.
DR ProteomicsDB; 273042; -.
DR ABCD; O08689; 5 sequenced antibodies.
DR Antibodypedia; 4098; 729 antibodies from 38 providers.
DR DNASU; 17700; -.
DR Ensembl; ENSMUST00000027269; ENSMUSP00000027269; ENSMUSG00000026100.
DR GeneID; 17700; -.
DR KEGG; mmu:17700; -.
DR UCSC; uc007ayt.1; mouse.
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; QICVYIY; -.
DR OrthoDB; 892873at2759; -.
DR PhylomeDB; O08689; -.
DR TreeFam; TF318514; -.
DR BioGRID-ORCS; 17700; 1 hit in 71 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 tissues.
DR ExpressionAtlas; O08689; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
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: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 protein kinase B signaling; 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:0010592; P:positive regulation of lamellipodium assembly; IMP:UniProtKB.
DR GO; GO:0010759; P:positive regulation of macrophage chemotaxis; IMP: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; ISO:MGI.
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; IDA:MGI.
DR Gene3D; 2.10.90.10; -; 1.
DR IDEAL; IID50111; -.
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..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
