ID BMP6_HUMAN Reviewed; 513 AA. AC P22004; Q5TCP3; DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1991, sequence version 1. DT 27-MAR-2024, entry version 208. DE RecName: Full=Bone morphogenetic protein 6; DE Short=BMP-6; DE AltName: Full=VG-1-related protein; DE Short=VG-1-R; DE Short=VGR-1; DE Flags: Precursor; GN Name=BMP6; Synonyms=VGR; 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=Bone; RX PubMed=2263636; DOI=10.1073/pnas.87.24.9843; RA Celeste A.J., Iannazzi J.A., Taylor R.C., Hewick R.M., Rosen V., Wang E.A., RA Wozney J.M.; RT "Identification of transforming growth factor beta family members present RT in bone-inductive protein purified from bovine bone."; RL Proc. Natl. Acad. Sci. U.S.A. 87:9843-9847(1990). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [3] RP FUNCTION. RX PubMed=33021694; DOI=10.1007/s10456-020-09748-4; RA Pulkkinen H.H., Kiema M., Lappalainen J.P., Toropainen A., Beter M., RA Tirronen A., Holappa L., Niskanen H., Kaikkonen M.U., Ylae-Herttuala S., RA Laakkonen J.P.; RT "BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell RT response to VEGF."; RL Angiogenesis 24:129-144(2021). RN [4] RP VARIANTS [LARGE SCALE ANALYSIS] ASP-343 AND LEU-476. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [5] RP FUNCTION, AND INTERACTION WITH MOUSE ERFE. RX PubMed=30097509; DOI=10.1182/blood-2018-06-857995; RA Arezes J., Foy N., McHugh K., Sawant A., Quinkert D., Terraube V., RA Brinth A., Tam M., LaVallie E.R., Taylor S., Armitage A.E., Pasricha S.R., RA Cunningham O., Lambert M., Draper S.J., Jasuja R., Drakesmith H.; RT "Erythroferrone inhibits the induction of hepcidin by BMP6."; RL Blood 132:1473-1477(2018). RN [6] RP FUNCTION, AND INTERACTION WITH MOUSE ERFE; MOUSE ACVR1; MOUSE BMPR1A AND RP BMP2. RX PubMed=31800957; DOI=10.1182/blood.2019002620; RA Wang C.Y., Xu Y., Traeger L., Dogan D.Y., Xiao X., Steinbicker A.U., RA Babitt J.L.; RT "Erythroferrone lowers hepcidin by sequestering BMP2/6 heterodimer from RT binding to the BMP type I receptor ALK3."; RL Blood 135:453-456(2020). RN [7] RP X-RAY CRYSTALLOGRAPHY (2.49 ANGSTROMS) OF 382-513. RX PubMed=17924656; DOI=10.1021/bi700907k; RA Allendorph G.P., Isaacs M.J., Kawakami Y., Izpisua Belmonte J.C., Choe S.; RT "BMP-3 and BMP-6 structures illuminate the nature of binding specificity RT with receptors."; RL Biochemistry 46:12238-12247(2007). RN [8] RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 397-513, DISULFIDE BONDS, RP GLYCOSYLATION AT ASN-454, INTERACTION WITH ACVR1 AND ACVR2B, AND FUNCTION. RX PubMed=18070108; DOI=10.1111/j.1742-4658.2007.06187.x; RA Saremba S., Nickel J., Seher A., Kotzsch A., Sebald W., Mueller T.D.; RT "Type I receptor binding of bone morphogenetic protein 6 is dependent on N- RT glycosylation of the ligand."; RL FEBS J. 275:172-183(2008). RN [9] RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 410-513, DISULFIDE BONDS, AND RP FUNCTION. RX PubMed=31019025; DOI=10.1126/scitranslmed.aar4953; RA Seeherman H.J., Berasi S.P., Brown C.T., Martinez R.X., Juo Z.S., RA Jelinsky S., Cain M.J., Grode J., Tumelty K.E., Bohner M., Grinberg O., RA Orr N., Shoseyov O., Eyckmans J., Chen C., Morales P.R., Wilson C.G., RA Vanderploeg E.J., Wozney J.M.; RT "A BMP/activin A chimera is superior to native BMPs and induces bone repair RT in nonhuman primates when delivered in a composite matrix."; RL Sci. Transl. Med. 11:0-0(2019). RN [10] RP VARIANTS IO SER-95; PRO-96 AND GLU-113, CHARACTERIZATION OF VARIANTS IO RP SER-95; PRO-96 AND GLU-113, INVOLVEMENT IN IO, FUNCTION, AND SUBCELLULAR RP LOCATION. RX PubMed=26582087; DOI=10.1053/j.gastro.2015.10.049; RA Daher R., Kannengiesser C., Houamel D., Lefebvre T., Bardou-Jacquet E., RA Ducrot N., de Kerguenec C., Jouanolle A.M., Robreau A.M., Oudin C., RA Le Gac G., Moulouel B., Loustaud-Ratti V., Bedossa P., Valla D., Gouya L., RA Beaumont C., Brissot P., Puy H., Karim Z., Tchernitchko D.; RT "Heterozygous Mutations in BMP6 pro-peptide lead to inappropriate hepcidin RT synthesis and moderate iron overload in humans."; RL Gastroenterology 150:672.e4-683.e4(2016). RN [11] RP VARIANTS IO SER-95 AND GLU-113. RX PubMed=27591421; DOI=10.1053/j.gastro.2016.02.088; RA Bignell P., Atoyebi W., Robson K.; RT "Heterozygous BMP6 variants coupled with HFE variants."; RL Gastroenterology 151:769-769(2016). RN [12] RP VARIANT IO PRO-96. RX PubMed=27590690; DOI=10.1053/j.gastro.2016.03.054; RA Le Gac G., Gourlaouen I., Ka C., Ferec C.; RT "The p.Leu96Pro missense mutation in the BMP6 gene is repeatedly associated RT with hyperferritinemia in patients of French origin."; RL Gastroenterology 151:769-770(2016). RN [13] RP VARIANTS IO PRO-96; GLN-112 AND HIS-257. RX PubMed=28335084; DOI=10.1002/ajh.24730; RA Piubelli C., Castagna A., Marchi G., Rizzi M., Busti F., Badar S., RA Marchetti M., De Gobbi M., Roetto A., Xumerle L., Suku E., Giorgetti A., RA Delledonne M., Olivieri O., Girelli D.; RT "Identification of new BMP6 pro-peptide mutations in patients with iron RT overload."; RL Am. J. Hematol. 92:562-568(2017). RN [14] RP VARIANTS IO 158-GLN--HIS-513 DEL; HIS-257 AND MET-394. RX PubMed=32464486; DOI=10.1016/j.bcmd.2020.102444; RA Alvarenga A.M., da Silva N.K., Fonseca P.F.S., Oliveira T.G.M., RA da Silva Monteiro J.B., Cancado R.D., Naoum F.A., Dinardo C.L., Brissot P., RA Santos P.C.J.L.; RT "Novel mutations in the bone morphogenetic protein 6 gene in patients with RT iron overload and non-homozygous genotype for the HFE p.Cys282Tyr RT mutation."; RL Blood Cells Mol. Dis. 84:102444-102444(2020). RN [15] RP VARIANTS IO PRO-96 AND GLU-113. RX PubMed=31640930; DOI=10.1016/j.clinre.2019.09.007; RA Borgel A., Lamoril J., Tchernitchko D.; RT "Mutations and polymorphisms associated with iron overload in a series of RT 91 non-HFE haemochromatosis patients."; RL Clin. Res. Hepatol. Gastroenterol. 44:239-241(2020). RN [16] RP VARIANT IO MET-394, AND CHARACTERIZATION OF VARIANT IO MET-394. RX PubMed=34037557; DOI=10.1097/meg.0000000000001971; RA Tchernitchko D., Lamoril J.; RT "Novel BMP6 gene mutation in patient with iron overload."; RL Eur. J. Gastroenterol. Hepatol. 33:1029-1030(2021). CC -!- FUNCTION: Growth factor of the TGF-beta superfamily that plays CC essential roles in many developmental processes including cartilage and CC bone formation (PubMed:31019025). Also plays an important role in the CC regulation of HAMP/hepcidin expression and iron metabolism by acting as CC a ligand for hemojuvelin/HJV (PubMed:26582087). Also acts to promote CC expression of HAMP, potentially via the interaction with its receptor CC BMPR1A/ALK3 (PubMed:30097509, PubMed:31800957). Initiates the canonical CC BMP signaling cascade by associating with type I receptor ACVR1 and CC type II receptor ACVR2B (PubMed:18070108). In turn, ACVR1 propagates CC signal by phosphorylating SMAD1/5/8 that travel to the nucleus and act CC as activators and repressors of transcription of target. Can also CC signal through non-canonical pathway such as TAZ-Hippo signaling CC cascade to modulate VEGF signaling by regulating VEGFR2 expression CC (PubMed:33021694). {ECO:0000269|PubMed:18070108, CC ECO:0000269|PubMed:26582087, ECO:0000269|PubMed:30097509, CC ECO:0000269|PubMed:31019025, ECO:0000269|PubMed:31800957, CC ECO:0000269|PubMed:33021694}. CC -!- SUBUNIT: Interacts with SOSTDC1 (By similarity). Interacts (when CC glycosylated) with type I receptor ACVR1; the interaction may induce CC HAMP expression (PubMed:31800957, PubMed:18070108). Interacts with type CC II receptor ACVR2B (PubMed:18070108). Interacts with Hemojuvelin/HJV CC (By similarity). Interacts with ERFE; the interaction inhibits BMP- CC induced transcription of HAMP (PubMed:30097509, PubMed:31800957). CC Interacts with BMPR1A/ALK3 (PubMed:31800957). Forms heterodimers with CC BMP2 in vitro; the heterodimer then binds to its receptor BMPR1A /ALK3 CC and may induce HAMP expression (PubMed:31800957). CC {ECO:0000250|UniProtKB:P20722, ECO:0000269|PubMed:18070108, CC ECO:0000269|PubMed:30097509, ECO:0000269|PubMed:31800957}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:26582087}. CC -!- PTM: Glycosylated at Asn-454. Glycosylation is crucial for recognition CC by the activin receptor type I/ACVR1. {ECO:0000269|PubMed:18070108}. CC -!- DISEASE: Iron overload (IO) [MIM:620121]: A disorder of iron CC homeostasis with incomplete and age-dependent penetrance. It is CC characterized by adult onset of increased hepatic and systemic iron CC levels, increased serum ferritin, normal or high transferrin CC saturation, and inappropriately low or normal levels of hepcidin. The CC severity of the phenotype depends on age, sex, as well as additional CC genetic or acquired factors including alcohol consumption and increased CC body weight. {ECO:0000269|PubMed:26582087, ECO:0000269|PubMed:27590690, CC ECO:0000269|PubMed:27591421, ECO:0000269|PubMed:28335084, CC ECO:0000269|PubMed:31640930, ECO:0000269|PubMed:32464486, CC ECO:0000269|PubMed:34037557}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the TGF-beta family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Bone morphogenetic protein 6 entry; CC URL="https://en.wikipedia.org/wiki/Bone_morphogenetic_protein_6"; 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; M60315; AAA36737.1; -; mRNA. DR EMBL; AL135778; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL133541; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS4503.1; -. DR PIR; B39263; BMHU6. DR RefSeq; NP_001709.1; NM_001718.5. DR PDB; 2QCW; X-ray; 2.49 A; A/B=382-513. DR PDB; 2R52; X-ray; 2.50 A; A/B=375-513. DR PDB; 2R53; X-ray; 2.10 A; A/B=411-513. DR PDB; 6OMO; X-ray; 2.80 A; I/J=410-513. DR PDBsum; 2QCW; -. DR PDBsum; 2R52; -. DR PDBsum; 2R53; -. DR PDBsum; 6OMO; -. DR AlphaFoldDB; P22004; -. DR SMR; P22004; -. DR BioGRID; 107122; 16. DR DIP; DIP-5797N; -. DR IntAct; P22004; 1. DR STRING; 9606.ENSP00000283147; -. DR BindingDB; P22004; -. DR ChEMBL; CHEMBL3286078; -. DR GlyCosmos; P22004; 5 sites, No reported glycans. DR GlyGen; P22004; 7 sites, 1 O-linked glycan (2 sites). DR iPTMnet; P22004; -. DR PhosphoSitePlus; P22004; -. DR BioMuta; BMP6; -. DR DMDM; 115076; -. DR MassIVE; P22004; -. DR MaxQB; P22004; -. DR PaxDb; 9606-ENSP00000283147; -. DR PeptideAtlas; P22004; -. DR ProteomicsDB; 53952; -. DR Pumba; P22004; -. DR Antibodypedia; 3456; 553 antibodies from 37 providers. DR DNASU; 654; -. DR Ensembl; ENST00000283147.7; ENSP00000283147.6; ENSG00000153162.9. DR GeneID; 654; -. DR KEGG; hsa:654; -. DR MANE-Select; ENST00000283147.7; ENSP00000283147.6; NM_001718.6; NP_001709.1. DR UCSC; uc003mxu.5; human. DR AGR; HGNC:1073; -. DR CTD; 654; -. DR DisGeNET; 654; -. DR GeneCards; BMP6; -. DR HGNC; HGNC:1073; BMP6. DR HPA; ENSG00000153162; Tissue enhanced (ovary). DR MalaCards; BMP6; -. DR MIM; 112266; gene. DR MIM; 620121; phenotype. DR neXtProt; NX_P22004; -. DR OpenTargets; ENSG00000153162; -. DR Orphanet; 465508; Symptomatic form of HFE-related hemochromatosis. DR PharmGKB; PA25383; -. DR VEuPathDB; HostDB:ENSG00000153162; -. DR eggNOG; KOG3900; Eukaryota. DR GeneTree; ENSGT00940000158768; -. DR HOGENOM; CLU_020515_4_1_1; -. DR InParanoid; P22004; -. DR OMA; ERQQPWP; -. DR OrthoDB; 2912454at2759; -. DR PhylomeDB; P22004; -. DR TreeFam; TF316134; -. DR PathwayCommons; P22004; -. DR SignaLink; P22004; -. DR BioGRID-ORCS; 654; 11 hits in 1148 CRISPR screens. DR ChiTaRS; BMP6; human. DR EvolutionaryTrace; P22004; -. DR GeneWiki; Bone_morphogenetic_protein_6; -. DR GenomeRNAi; 654; -. DR Pharos; P22004; Tbio. DR PRO; PR:P22004; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; P22004; Protein. DR Bgee; ENSG00000153162; Expressed in secondary oocyte and 123 other cell types or tissues. DR GO; GO:0005615; C:extracellular space; IMP:UniProtKB. DR GO; GO:0031982; C:vesicle; IEA:Ensembl. DR GO; GO:0070700; F:BMP receptor binding; IDA:MGI. DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central. DR GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW. DR GO; GO:0046982; F:protein heterodimerization activity; IDA:MGI. DR GO; GO:0030509; P:BMP signaling pathway; IDA:BHF-UCL. DR GO; GO:0060348; P:bone development; IDA:BHF-UCL. DR GO; GO:0051216; P:cartilage development; IEA:UniProtKB-KW. DR GO; GO:0071773; P:cellular response to BMP stimulus; IMP:BHF-UCL. DR GO; GO:0071281; P:cellular response to iron ion; ISS:BHF-UCL. DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl. DR GO; GO:0001958; P:endochondral ossification; IEA:Ensembl. DR GO; GO:0001654; P:eye development; IEA:Ensembl. DR GO; GO:0006955; P:immune response; IMP:BHF-UCL. DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl. DR GO; GO:0006879; P:intracellular iron ion homeostasis; ISS:BHF-UCL. DR GO; GO:0001822; P:kidney development; IEA:Ensembl. DR GO; GO:0030539; P:male genitalia development; IEA:Ensembl. DR GO; GO:0060586; P:multicellular organismal-level iron ion homeostasis; IMP:UniProtKB. DR GO; GO:1903392; P:negative regulation of adherens junction organization; IDA:ARUK-UCL. DR GO; GO:2000048; P:negative regulation of cell-cell adhesion mediated by cadherin; IDA:ARUK-UCL. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:BHF-UCL. DR GO; GO:0030182; P:neuron differentiation; IEA:Ensembl. DR GO; GO:0001649; P:osteoblast differentiation; IEA:Ensembl. DR GO; GO:0032349; P:positive regulation of aldosterone biosynthetic process; IDA:UniProtKB. DR GO; GO:2000860; P:positive regulation of aldosterone secretion; IEA:Ensembl. DR GO; GO:0030501; P:positive regulation of bone mineralization; IDA:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell population proliferation; NAS:BHF-UCL. DR GO; GO:0032332; P:positive regulation of chondrocyte differentiation; IEA:Ensembl. DR GO; GO:0045603; P:positive regulation of endothelial cell differentiation; IEA:Ensembl. DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IEA:Ensembl. DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IDA:BHF-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL. DR GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; ISS:BHF-UCL. DR GO; GO:0045666; P:positive regulation of neuron differentiation; IEA:Ensembl. DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; IDA:BHF-UCL. DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:ARUK-UCL. DR GO; GO:0050714; P:positive regulation of protein secretion; NAS:BHF-UCL. DR GO; GO:0060391; P:positive regulation of SMAD protein signal transduction; IDA:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0043117; P:positive regulation of vascular permeability; IDA:ARUK-UCL. DR GO; GO:0014823; P:response to activity; IEA:Ensembl. DR GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl. DR GO; GO:0032026; P:response to magnesium ion; IEA:Ensembl. DR GO; GO:0032526; P:response to retinoic acid; IEA:Ensembl. DR GO; GO:0001501; P:skeletal system development; TAS:ProtInc. DR GO; GO:0003323; P:type B pancreatic cell development; IDA:BHF-UCL. DR CDD; cd19396; TGF_beta_BMP6; 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:SF137; BONE MORPHOGENETIC PROTEIN 6; 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; P22004; HS. PE 1: Evidence at protein level; KW 3D-structure; Chondrogenesis; Cleavage on pair of basic residues; Cytokine; KW Developmental protein; Differentiation; Disease variant; Disulfide bond; KW Glycoprotein; Growth factor; Osteogenesis; Reference proteome; Secreted; KW Signal. FT SIGNAL 1..20 FT /evidence="ECO:0000255" FT PROPEP 21..374 FT /evidence="ECO:0000255" FT /id="PRO_0000033870" FT CHAIN 375..513 FT /note="Bone morphogenetic protein 6" FT /id="PRO_0000033871" FT REGION 38..66 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 89..131 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 145..200 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 373..398 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 103..121 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 160..174 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 382..398 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 241 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 269 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 386 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 404 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 454 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:18070108" FT DISULFID 412..478 FT /evidence="ECO:0000269|PubMed:18070108, FT ECO:0000269|PubMed:31019025" FT DISULFID 441..510 FT /evidence="ECO:0000269|PubMed:18070108, FT ECO:0000269|PubMed:31019025" FT DISULFID 445..512 FT /evidence="ECO:0000269|PubMed:18070108, FT ECO:0000269|PubMed:31019025" FT DISULFID 477 FT /note="Interchain" FT /evidence="ECO:0000269|PubMed:18070108, FT ECO:0000269|PubMed:31019025" FT VARIANT 95 FT /note="P -> S (in IO; associated with disease FT susceptibility; some patients also carry a HFE variant; FT decreased function in positive regulation of SMAD protein FT signal transduction; results in partial activation of FT hepcidin expression; affects post-translational processing FT resulting in reduced amount of the mature form; results in FT impaired secretion; dbSNP:rs199518216)" FT /evidence="ECO:0000269|PubMed:26582087, FT ECO:0000269|PubMed:27591421" FT /id="VAR_087884" FT VARIANT 96 FT /note="L -> P (in IO; associated with disease FT susceptibility; some patients also carry a HFE variant; FT decreased function in positive regulation of SMAD protein FT signal transduction; results in partial activation of FT hepcidin expression; affects post-translational processing FT resulting in reduced amount of the mature form; results in FT impaired secretion; dbSNP:rs200573175)" FT /evidence="ECO:0000269|PubMed:26582087, FT ECO:0000269|PubMed:27590690, ECO:0000269|PubMed:28335084, FT ECO:0000269|PubMed:31640930" FT /id="VAR_087885" FT VARIANT 112 FT /note="E -> Q (in IO; associated with disease FT susceptibility; dbSNP:rs201486498)" FT /evidence="ECO:0000269|PubMed:28335084" FT /id="VAR_087886" FT VARIANT 113 FT /note="Q -> E (in IO; associated with disease FT susceptibility; some patients also carry a HFE variant; FT decreased function in positive regulation of SMAD protein FT signal transduction; results in partial activation of FT hepcidin expression; affects post-translational processing FT resulting in reduced amount of the mature form; results in FT impaired secretion; dbSNP:rs7745236)" FT /evidence="ECO:0000269|PubMed:26582087, FT ECO:0000269|PubMed:27591421, ECO:0000269|PubMed:31640930" FT /id="VAR_087887" FT VARIANT 158..513 FT /note="Missing (in IO; associated with disease FT susceptibility)" FT /evidence="ECO:0000269|PubMed:32464486" FT /id="VAR_087888" FT VARIANT 257 FT /note="R -> C (in dbSNP:rs10458105)" FT /id="VAR_047055" FT VARIANT 257 FT /note="R -> H (in IO; associated with disease FT susceptibility; dbSNP:rs148916269)" FT /evidence="ECO:0000269|PubMed:28335084, FT ECO:0000269|PubMed:32464486" FT /id="VAR_087889" FT VARIANT 343 FT /note="A -> D (in a colorectal cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036200" FT VARIANT 394 FT /note="V -> M (in IO; associated with disease FT susceptibility; results in decreased activation of hepcidin FT expression in cultured liver cells; dbSNP:rs142167481)" FT /evidence="ECO:0000269|PubMed:32464486, FT ECO:0000269|PubMed:34037557" FT /id="VAR_087890" FT VARIANT 476 FT /note="P -> L (in a colorectal cancer sample; somatic FT mutation; dbSNP:rs909733732)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036201" FT STRAND 411..415 FT /evidence="ECO:0007829|PDB:2R53" FT STRAND 418..420 FT /evidence="ECO:0007829|PDB:2R53" FT TURN 421..425 FT /evidence="ECO:0007829|PDB:2R53" FT TURN 427..429 FT /evidence="ECO:0007829|PDB:2R53" FT STRAND 430..432 FT /evidence="ECO:0007829|PDB:2R53" FT STRAND 434..437 FT /evidence="ECO:0007829|PDB:2R53" FT STRAND 440..442 FT /evidence="ECO:0007829|PDB:2R53" FT TURN 451..454 FT /evidence="ECO:0007829|PDB:2R53" FT HELIX 457..468 FT /evidence="ECO:0007829|PDB:2R53" FT TURN 470..472 FT /evidence="ECO:0007829|PDB:2R53" FT STRAND 477..491 FT /evidence="ECO:0007829|PDB:2R53" FT STRAND 497..513 FT /evidence="ECO:0007829|PDB:2R53" SQ SEQUENCE 513 AA; 57226 MW; 3F19155B36049278 CRC64; MPGLGRRAQW LCWWWGLLCS CCGPPPLRPP LPAAAAAAAG GQLLGDGGSP GRTEQPPPSP QSSSGFLYRR LKTQEKREMQ KEILSVLGLP HRPRPLHGLQ QPQPPALRQQ EEQQQQQQLP RGEPPPGRLK SAPLFMLDLY NALSADNDED GASEGERQQS WPHEAASSSQ RRQPPPGAAH PLNRKSLLAP GSGSGGASPL TSAQDSAFLN DADMVMSFVN LVEYDKEFSP RQRHHKEFKF NLSQIPEGEV VTAAEFRIYK DCVMGSFKNQ TFLISIYQVL QEHQHRDSDL FLLDTRVVWA SEEGWLEFDI TATSNLWVVT PQHNMGLQLS VVTRDGVHVH PRAAGLVGRD GPYDKQPFMV AFFKVSEVHV RTTRSASSRR RQQSRNRSTQ SQDVARVSSA SDYNSSELKT ACRKHELYVS FQDLGWQDWI IAPKGYAANY CDGECSFPLN AHMNATNHAI VQTLVHLMNP EYVPKPCCAP TKLNAISVLY FDDNSNVILK KYRNMVVRAC GCH //