ID OSTCN_HUMAN Reviewed; 100 AA. AC P02818; Q5TCK6; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1990, sequence version 2. DT 24-JAN-2024, entry version 195. DE RecName: Full=Osteocalcin; DE AltName: Full=Bone Gla protein {ECO:0000303|PubMed:2336375}; DE Short=BGP; DE AltName: Full=Gamma-carboxyglutamic acid-containing protein; DE Flags: Precursor; GN Name=BGLAP; 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 [GENOMIC DNA], AND FUNCTION. RX PubMed=3019668; DOI=10.1002/j.1460-2075.1986.tb04440.x; RA Celeste A.J., Buecker J.L., Kriz R., Wang E.A., Wozney J.M.; RT "Isolation of the human gene for bone gla protein utilizing mouse and rat RT cDNA clones."; RL EMBO J. 5:1885-1890(1986). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2336375; DOI=10.1093/nar/18.7.1909; RA Kiefer M.C., Saphire A.C.S., Bauer D.M., Barr P.J.; RT "The cDNA and derived amino acid sequences of human and bovine bone Gla RT protein."; RL Nucleic Acids Res. 18:1909-1909(1990). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLN-94. RG SeattleSNPs variation discovery resource; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [7] RP PROTEIN SEQUENCE OF 52-100, FUNCTION, SUBCELLULAR LOCATION, RP GAMMA-CARBOXYGLUTAMATION AT GLU-68; GLU-72 AND GLU-75, AND LACK OF RP HYDROXYLATION AT PRO-60. RX PubMed=6967872; DOI=10.1016/s0021-9258(18)43554-5; RA Poser J.W., Esch F.S., Ling N.C., Price P.A.; RT "Isolation and sequence of the vitamin K-dependent protein from human bone. RT Undercarboxylation of the first glutamic acid residue."; RL J. Biol. Chem. 255:8685-8691(1980). CC -!- FUNCTION: Bone protein that constitutes 1-2% of the total bone protein, CC and which acts as a negative regulator of bone formation CC (PubMed:3019668, PubMed:6967872). Functions to limit bone formation CC without impairing bone resorption or mineralization (By similarity). It CC binds strongly to apatite and calcium (PubMed:6967872). CC {ECO:0000250|UniProtKB:P86546, ECO:0000269|PubMed:3019668, CC ECO:0000269|PubMed:6967872}. CC -!- FUNCTION: The uncarboxylated form acts as a hormone secreted by CC osteoblasts, which regulates different cellular processes, such as CC energy metabolism, male fertility and brain development. Regulates of CC energy metabolism by acting as a hormone favoring pancreatic beta-cell CC proliferation, insulin secretion and sensitivity and energy CC expenditure. Uncarboxylated osteocalcin hormone also promotes CC testosterone production in the testes: acts as a ligand for G protein- CC coupled receptor GPRC6A at the surface of Leydig cells, initiating a CC signaling response that promotes the expression of enzymes required for CC testosterone synthesis in a CREB-dependent manner. Also acts as a CC regulator of brain development: osteocalcin hormone crosses the blood- CC brain barrier and acts as a ligand for GPR158 on neurons, initiating a CC signaling response that prevents neuronal apoptosis in the hippocampus, CC favors the synthesis of all monoamine neurotransmitters and inhibits CC that of gamma-aminobutyric acid (GABA). Osteocalcin also crosses the CC placenta during pregnancy and maternal osteocalcin is required for CC fetal brain development. {ECO:0000250|UniProtKB:P86546}. CC -!- INTERACTION: CC P02818; Q12797-6: ASPH; NbExp=3; IntAct=EBI-12927282, EBI-12092171; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:6967872}. CC -!- PTM: Gamma-carboxyglutamate residues are formed by vitamin K dependent CC carboxylation by GGCX. These residues are essential for the binding of CC calcium (By similarity) (PubMed:6967872). Decarboxylation promotes the CC hormone activity (By similarity). {ECO:0000250|UniProtKB:P86546, CC ECO:0000255|PROSITE-ProRule:PRU00463, ECO:0000269|PubMed:6967872}. CC -!- SIMILARITY: Belongs to the osteocalcin/matrix Gla protein family. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Osteocalcin entry; CC URL="https://en.wikipedia.org/wiki/Osteocalcin"; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/bglap/"; 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; X04143; CAA27763.1; -; Genomic_DNA. DR EMBL; X53698; CAA37736.1; -; mRNA. DR EMBL; X51699; CAA35996.1; -; mRNA. DR EMBL; DQ007079; AAY16981.1; -; Genomic_DNA. DR EMBL; AL135927; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471121; EAW52986.1; -; Genomic_DNA. DR EMBL; BC113432; AAI13433.1; -; mRNA. DR EMBL; BC113434; AAI13435.1; -; mRNA. DR CCDS; CCDS1134.1; -. DR PIR; S12652; GEHU. DR RefSeq; NP_954642.1; NM_199173.5. DR AlphaFoldDB; P02818; -. DR SMR; P02818; -. DR BioGRID; 107101; 16. DR IntAct; P02818; 1. DR STRING; 9606.ENSP00000357255; -. DR DrugBank; DB05260; Gallium nitrate. DR DrugBank; DB03847; gamma-carboxy-L-glutamic acid. DR DrugBank; DB00170; Menadione. DR DrugBank; DB01022; Phylloquinone. DR BioMuta; BGLAP; -. DR DMDM; 129253; -. DR MassIVE; P02818; -. DR PaxDb; 9606-ENSP00000357255; -. DR PeptideAtlas; P02818; -. DR ProteomicsDB; 51606; -. DR ABCD; P02818; 5 sequenced antibodies. DR Antibodypedia; 34848; 1069 antibodies from 40 providers. DR DNASU; 632; -. DR Ensembl; ENST00000368272.5; ENSP00000357255.4; ENSG00000242252.2. DR GeneID; 632; -. DR KEGG; hsa:632; -. DR MANE-Select; ENST00000368272.5; ENSP00000357255.4; NM_199173.6; NP_954642.1. DR UCSC; uc001fnt.4; human. DR AGR; HGNC:1043; -. DR CTD; 632; -. DR DisGeNET; 632; -. DR GeneCards; BGLAP; -. DR HGNC; HGNC:1043; BGLAP. DR HPA; ENSG00000242252; Tissue enhanced (choroid plexus, intestine). DR MIM; 112260; gene. DR neXtProt; NX_P02818; -. DR OpenTargets; ENSG00000242252; -. DR PharmGKB; PA25345; -. DR VEuPathDB; HostDB:ENSG00000242252; -. DR eggNOG; ENOG502S85I; Eukaryota. DR GeneTree; ENSGT00410000026290; -. DR HOGENOM; CLU_160110_0_0_1; -. DR InParanoid; P02818; -. DR OMA; DQIGFQE; -. DR OrthoDB; 4841862at2759; -. DR PhylomeDB; P02818; -. DR TreeFam; TF330920; -. DR PathwayCommons; P02818; -. DR Reactome; R-HSA-159740; Gamma-carboxylation of protein precursors. DR Reactome; R-HSA-159763; Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus. DR Reactome; R-HSA-159782; Removal of aminoterminal propeptides from gamma-carboxylated proteins. DR Reactome; R-HSA-8940973; RUNX2 regulates osteoblast differentiation. DR SignaLink; P02818; -. DR SIGNOR; P02818; -. DR BioGRID-ORCS; 632; 22 hits in 1149 CRISPR screens. DR GeneWiki; Osteocalcin; -. DR GenomeRNAi; 632; -. DR Pharos; P02818; Tbio. DR PRO; PR:P02818; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; P02818; Protein. DR Bgee; ENSG00000242252; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 94 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0030425; C:dendrite; IEA:Ensembl. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0005576; C:extracellular region; ISS:UniProt. DR GO; GO:0005615; C:extracellular space; IEA:Ensembl. DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome. DR GO; GO:0043204; C:perikaryon; IEA:Ensembl. DR GO; GO:0031982; C:vesicle; IEA:Ensembl. DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro. DR GO; GO:0005179; F:hormone activity; ISS:UniProtKB. DR GO; GO:0046848; F:hydroxyapatite binding; IBA:GO_Central. DR GO; GO:0008147; F:structural constituent of bone; ISS:UniProtKB. DR GO; GO:0005198; F:structural molecule activity; NAS:ProtInc. DR GO; GO:0060348; P:bone development; IBA:GO_Central. DR GO; GO:0030282; P:bone mineralization; NAS:UniProtKB. DR GO; GO:0007420; P:brain development; ISS:UniProtKB. DR GO; GO:0007155; P:cell adhesion; NAS:UniProtKB. DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl. DR GO; GO:0032869; P:cellular response to insulin stimulus; ISS:UniProtKB. DR GO; GO:0071305; P:cellular response to vitamin D; IEA:Ensembl. DR GO; GO:0034224; P:cellular response to zinc ion starvation; IEA:Ensembl. DR GO; GO:0050890; P:cognition; ISS:UniProtKB. DR GO; GO:0016311; P:dephosphorylation; IEA:Ensembl. DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB. DR GO; GO:0007611; P:learning or memory; ISS:UniProtKB. DR GO; GO:1903011; P:negative regulation of bone development; ISS:UniProtKB. DR GO; GO:0002076; P:osteoblast development; IEA:Ensembl. DR GO; GO:0001649; P:osteoblast differentiation; IEP:BHF-UCL. DR GO; GO:0001956; P:positive regulation of neurotransmitter secretion; ISS:UniProtKB. DR GO; GO:0030500; P:regulation of bone mineralization; IEA:InterPro. DR GO; GO:0045124; P:regulation of bone resorption; NAS:UniProtKB. DR GO; GO:1900076; P:regulation of cellular response to insulin stimulus; IEA:InterPro. DR GO; GO:0045670; P:regulation of osteoclast differentiation; NAS:UniProtKB. DR GO; GO:2000224; P:regulation of testosterone biosynthetic process; ISS:UniProtKB. DR GO; GO:0014823; P:response to activity; 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:0051384; P:response to glucocorticoid; IEA:Ensembl. DR GO; GO:0009629; P:response to gravity; IEA:Ensembl. DR GO; GO:0033594; P:response to hydroxyisoflavone; IEA:Ensembl. DR GO; GO:0036005; P:response to macrophage colony-stimulating factor; IEA:Ensembl. DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl. DR GO; GO:0033574; P:response to testosterone; IEA:Ensembl. DR GO; GO:0033280; P:response to vitamin D; IEP:BHF-UCL. DR GO; GO:0032571; P:response to vitamin K; IEA:Ensembl. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0010043; P:response to zinc ion; IEA:Ensembl. DR GO; GO:0001501; P:skeletal system development; TAS:ProtInc. DR GO; GO:0048863; P:stem cell differentiation; IEA:Ensembl. DR GO; GO:0044342; P:type B pancreatic cell proliferation; ISS:UniProtKB. DR InterPro; IPR035972; GLA-like_dom_SF. DR InterPro; IPR000294; GLA_domain. DR InterPro; IPR039176; Osteocalcin. DR InterPro; IPR002384; Osteocalcin/MGP. DR PANTHER; PTHR14235; OSTEOCALCIN; 1. DR PANTHER; PTHR14235:SF0; OSTEOCALCIN; 1. DR PRINTS; PR00002; GLABONE. DR SMART; SM00069; GLA; 1. DR SUPFAM; SSF57630; GLA-domain; 1. DR PROSITE; PS00011; GLA_1; 1. DR PROSITE; PS50998; GLA_2; 1. DR Genevisible; P02818; HS. PE 1: Evidence at protein level; KW Biomineralization; Calcium; Cleavage on pair of basic residues; KW Direct protein sequencing; Disulfide bond; Gamma-carboxyglutamic acid; KW Hormone; Metal-binding; Reference proteome; Secreted; Signal. FT SIGNAL 1..23 FT /evidence="ECO:0000305" FT PROPEP 24..51 FT /evidence="ECO:0000305|PubMed:6967872" FT /id="PRO_0000011086" FT CHAIN 52..100 FT /note="Osteocalcin" FT /evidence="ECO:0000269|PubMed:6967872" FT /id="PRO_0000011087" FT DOMAIN 52..98 FT /note="Gla" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463" FT BINDING 68 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P02820" FT BINDING 72 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P02820" FT BINDING 75 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P02820" FT BINDING 75 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" FT /evidence="ECO:0000250|UniProtKB:P02820" FT BINDING 81 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" FT /evidence="ECO:0000250|UniProtKB:P02820" FT SITE 60 FT /note="Not hydroxylated" FT /evidence="ECO:0000269|PubMed:6967872" FT MOD_RES 68 FT /note="4-carboxyglutamate; partial" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:6967872" FT MOD_RES 72 FT /note="4-carboxyglutamate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:6967872" FT MOD_RES 75 FT /note="4-carboxyglutamate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:6967872" FT DISULFID 74..80 FT /evidence="ECO:0000305|PubMed:6967872" FT VARIANT 94 FT /note="R -> Q (in dbSNP:rs34702397)" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_038743" FT CONFLICT 33..34 FT /note="Missing (in Ref. 1; CAA27763)" FT /evidence="ECO:0000305" SQ SEQUENCE 100 AA; 10963 MW; 4DF2A0A80849CB71 CRC64; MRALTLLALL ALAALCIAGQ AGAKPSGAES SKGAAFVSKQ EGSEVVKRPR RYLYQWLGAP VPYPDPLEPR REVCELNPDC DELADHIGFQ EAYRRFYGPV //