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/";
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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 Genevisible; P02818; HS.
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.
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
//
