Vitamin D-binding protein

GC
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1J78, 1J7E, 1KW2, 1KXP, 1LOT, 1MA9
Identifiers
Aliases	GC , DBP, DBP/GRD3, HEL-S-51, VDBG, VDBP, Gc-MAF, GcMAF, vitamin D binding protein, DBP-maf, VDB, GC vitamin D binding protein
External IDs	OMIM: 139200; MGI: 95669; HomoloGene: 486; GeneCards: GC; OMA:GC - orthologs
Gene location (Human) Chr. Chromosome 4 (human) [1] Band 4q13.3 Start 71,741,696 bp [1] End 71,804,041 bp [1]
Gene location (Mouse) Chr. Chromosome 5 (mouse) [2] Band 5 E1|5 44.32 cM Start 89,565,381 bp [2] End 89,605,757 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in liver right lobe of liver gallbladder pancreatic ductal cell beta cell duodenum body of pancreas jejunal mucosa testicle gonad Top expressed in left lobe of liver gallbladder islet of Langerhans fetal liver hematopoietic progenitor cell human fetus right kidney human kidney sexually immature organism morula stomach More reference expression data BioGPS More reference expression data
Gene ontology Molecular function vitamin D binding calcidiol binding actin binding vitamin transmembrane transporter activity Cellular component blood microparticle extracellular region lysosomal lumen extracellular exosome extracellular space cytosol Biological process vitamin D metabolic process vitamin transport transport vitamin transmembrane transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2638 14473 Ensembl ENSG00000145321 ENSMUSG00000035540 UniProt P02774 P21614 RefSeq (mRNA) NM_000583 NM_001204306 NM_001204307 NM_008096 RefSeq (protein) NP_000574 NP_001191235 NP_001191236 NP_032122 Location (UCSC) Chr 4: 71.74 – 71.8 Mb Chr 5: 89.57 – 89.61 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Vitamin D-binding protein (DBP), also/originally known as gc-globulin (group-specific component), is a protein that in humans is encoded by the GC gene. ^{[5] [6]} DBP is genetically the oldest member of the albuminoid family and appeared early in the evolution of vertebrates. ^[7]

Structure

Human GC is a glycosylated alpha-globulin, ~58 kDa in size. Its 458 amino acids are coded for by 1690 nucleotides on chromosome 4 (4q11–q13). The primary structure contains 28 cysteine residues forming multiple disulfide bonds. GC contains 3 domains. Domain 1 is composed of 10 alpha helices, domain 2 of 9, and domain 3 of 4. ^[8]

Function

Vitamin D-binding protein belongs to the albumin gene family, together with human serum albumin and alpha-fetoprotein. It is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid and on the surface of many cell types.

It is able to bind the various forms of vitamin D including ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃), the 25-hydroxylated forms (calcifediol), and the active hormonal product, 1,25-dihydroxyvitamin D (calcitriol). The major proportion of vitamin D in blood is bound to this protein. It transports vitamin D metabolites between skin, liver and kidney, and then on to the various target tissues. ^{[6] [9]}

Beyond acting as the carrier protein for vitamin D and its metabolites, DBP also transports free fatty acids, ^[10] binds to actin ^[11] and may help prevent actin polymerization during tissue injury. ^[12] It also might serve as a macrophage activator, contributing to the inflammatory response by modulating T-cell activity. ^[13]

As Gc protein-derived macrophage activating factor it is a Macrophage Activating Factor (MAF) that has been tested for use as a cancer treatment that would activate macrophages against cancer cells. ^[14]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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Vitamin D Synthesis Pathway (view / edit)

1. The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".

Production

It is synthesized by hepatic parenchymal cells and secreted into the blood circulation. ^[9]

Regulation

The transcription factors HFN1α is a positive regulator while HFN1β is a dominant negative regulator of DBP expression. ^[15]

Evolution

Phylogenetic analyses suggest that DBP diverged from ancestral albumin through gene duplication events that occurred after the separation of jawless fish (cyclostomes) from jawed vertebrates approximately 450 million years ago. ^[16] This timeline is supported by the apparent absence of DBP-like proteins in lampreys and hagfish, though these organisms retain vitamin D transport capability through alternative lipoprotein-mediated mechanisms. ^[17] DBP is found throughout jawed vertebrates, from bony fish to mammals, suggesting its evolution coincided with the development of calcified skeletons and more sophisticated calcium homeostasis requirements. ^[18]

Variation

Many genetic variants of the GC gene are known. They produce 6 main haplotypes and 3 main protein variants (Gc1S, Gc1F and Gc2). ^[19] The genetic variations are associated with differences in circulating 25-hydroxyvitamin D levels. ^[20] They have been proposed to account for some of the differences in vitamin D status in different ethnic groups, ^[21] and have been found to correlate with the response to vitamin D supplementation. ^[19]

References

1. GRCh38: Ensembl release 89: ENSG00000145321 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000035540 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Mikkelsen M, Jacobsen P, Henningsen K (Jul 1977). "Possible localization of Gc-System on chromosome 4. Loss of long arm 4 material associated with father-child incompatibility within the Gc-System". Human Heredity. 27 (2): 105–107. doi:10.1159/000152857. PMID   558959.
6. "Entrez Gene: GC group-specific component (vitamin D binding protein)".
7. Bouillon R, Schuit F, Antonio L, Rastinejad F (2020). "Vitamin D Binding Protein: A Historic Overview". Frontiers in Endocrinology. 10 910. doi: 10.3389/fendo.2019.00910 . PMC   6965021 . PMID   31998239.
8. Verboven C, Rabijns A, De Maeyer M, Van Baelen H, Bouillon R, De Ranter C (February 2002). "A structural basis for the unique binding features of the human vitamin D-binding protein". Nature Structural Biology. 9 (2): 131–136. doi:10.1038/nsb754. PMID   11799400. S2CID   38990672.
9. Norman AW (August 2008). "From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health". The American Journal of Clinical Nutrition. 88 (2): 491S –499S. doi: 10.1093/ajcn/88.2.491S . PMID   18689389.
10. Williams MH, Van Alstyne EL, Galbraith RM (June 1988). "Evidence of a novel association of unsaturated fatty acids with Gc (vitamin D-binding protein)". Biochemical and Biophysical Research Communications. 153 (3): 1019–1024. doi:10.1016/S0006-291X(88)81330-5. PMID   3134016.
11. Van Baelen H, Bouillon R, De Moor P (1980). "Vitamin D-binding protein (Gc-globulin) binds actin". Journal of Biological Chemistry. 255 (6): 2270–2272. doi: 10.1016/S0021-9258(19)85885-4 . PMID   6892638.
12. Meier U, Gressner O, Lammert F, Gressner AM (July 2006). "Gc-globulin: roles in response to injury". Clinical Chemistry. 52 (7): 1247–1253. doi:10.1373/clinchem.2005.065680. PMID   16709624.
13. Delanghe JR, Speeckaert R, Speeckaert MM (October 2015). "Behind the scenes of vitamin D binding protein: more than vitamin D binding". Best Practice & Research. Clinical Endocrinology & Metabolism. 29 (5): 773–786. doi:10.1016/j.beem.2015.06.006. PMID   26522461.
14. Yamamoto N, Suyama H, Yamamoto N (July 2008). "Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF" ([PDF]). Translational Oncology. 1 (2): 65–72. doi:10.1593/tlo.08106. PMC   2510818 . PMID   18633461.
15. Bouillon R, Schuit F, Antonio L, Rastinejad F (2019). "Vitamin D Binding Protein: A Historic Overview". Frontiers in Endocrinology. 10 910. doi: 10.3389/fendo.2019.00910 . PMC   6965021 . PMID   31998239.
16. Gray JE, Doolittle RF (February 1992). "Characterization, primary structure, and evolution of lamprey plasma albumin". Protein Science. 1 (2): 289–302. doi:10.1002/pro.5560010211. PMC   2142188 . PMID   1304910.
17. Hay AW, Watson G (1976). "The plasma transport proteins of 25-hydroxycholecalciferol in fish, amphibians, reptiles and birds". Comparative Biochemistry and Physiology. B, Comparative Biochemistry. 53 (2): 167–172. doi:10.1016/0305-0491(76)90029-8. PMID   1253553.
18. Andreeva AM (2022). "Evolutionary Transformations of Albumin Using the Example of Model Species of Jawless Agnatha and Bony Jawed Fish (Review)". Inland Water Biology. 15 (5): 641–658. doi: 10.1134/S1995082922050029 . ISSN   1995-0829.
19. Malik S, Fu L, Juras DJ, Karmali M, Wong BY, Gozdzik A, et al. (January–February 2013). "Common variants of the vitamin D binding protein gene and adverse health outcomes". Critical Reviews in Clinical Laboratory Sciences. 50 (1): 1–22. doi:10.3109/10408363.2012.750262. PMC   3613945 . PMID   23427793.
20. McGrath JJ, Saha S, Burne TH, Eyles DW (July 2010). "A systematic review of the association between common single nucleotide polymorphisms and 25-hydroxyvitamin D concentrations". The Journal of Steroid Biochemistry and Molecular Biology. 121 (1–2): 471–477. doi:10.1016/j.jsbmb.2010.03.073. PMID   20363324. S2CID   20057294.
21. Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, et al. (November 2013). "Vitamin D-binding protein and vitamin D status of black Americans and white Americans". The New England Journal of Medicine. 369 (21): 1991–2000. doi:10.1056/NEJMoa1306357. PMC   4030388 . PMID   24256378.

Further reading

• Svasti J, Kurosky A, Bennett A, Bowman BH (April 1979). "Molecular basis for the three major forms of human serum vitamin D binding protein (group-specific component)". Biochemistry. 18 (8): 1611–1617. doi:10.1021/bi00575a036. PMID   218624.
• Braun A, Bichlmaier R, Cleve H (June 1992). "Molecular analysis of the gene for the human vitamin-D-binding protein (group-specific component): allelic differences of the common genetic GC types". Human Genetics. 89 (4): 401–406. doi:10.1007/BF00194311. PMID   1352271. S2CID   1913655.
• Esteban C, Geuskens M, Ena JM, Mishal Z, Macho A, Torres JM, et al. (May 1992). "Receptor-mediated uptake and processing of vitamin D-binding protein in human B-lymphoid cells". The Journal of Biological Chemistry. 267 (14): 10177–10183. doi: 10.1016/S0021-9258(19)50216-2 . PMID   1374401.
• Szpirer C, Riviere M, Cortese R, Nakamura T, Islam MQ, Levan G, et al. (June 1992). "Chromosomal localization in man and rat of the genes encoding the liver-enriched transcription factors C/EBP, DBP, and HNF1/LFB-1 (CEBP, DBP, and transcription factor 1, TCF1, respectively) and of the hepatocyte growth factor/scatter factor gene (HGF)". Genomics. 13 (2): 293–300. doi:10.1016/0888-7543(92)90245-N. PMID   1535333.
• Dawson SJ, White LA (May 1992). "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". The Journal of Infection. 24 (3): 317–320. doi:10.1016/S0163-4453(05)80037-4. PMID   1602151.
• Yang F, Bergeron JM, Linehan LA, Lalley PA, Sakaguchi AY, Bowman BH (August 1990). "Mapping and conservation of the group-specific component gene in mouse". Genomics. 7 (4): 509–516. doi:10.1016/0888-7543(90)90193-X. PMID   1696927.
• Yang F, Luna VJ, McAnelly RD, Naberhaus KH, Cupples RL, Bowman BH (November 1985). "Evolutionary and structural relationships among the group-specific component, albumin and alpha-fetoprotein". Nucleic Acids Research. 13 (22): 8007–8017. doi:10.1093/nar/13.22.8007. PMC   322106 . PMID   2415926.
• Yang F, Brune JL, Naylor SL, Cupples RL, Naberhaus KH, Bowman BH (December 1985). "Human group-specific component (Gc) is a member of the albumin family". Proceedings of the National Academy of Sciences of the United States of America. 82 (23): 7994–7998. Bibcode:1985PNAS...82.7994Y. doi: 10.1073/pnas.82.23.7994 . PMC   391428 . PMID   2415977.
• Cooke NE, David EV (December 1985). "Serum vitamin D-binding protein is a third member of the albumin and alpha fetoprotein gene family". The Journal of Clinical Investigation. 76 (6): 2420–2424. doi:10.1172/JCI112256. PMC   424397 . PMID   2416779.
• Schoentgen F, Metz-Boutigue MH, Jollès J, Constans J, Jollès P (June 1986). "Complete amino acid sequence of human vitamin D-binding protein (group-specific component): evidence of a three-fold internal homology as in serum albumin and alpha-fetoprotein". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 871 (2): 189–198. doi:10.1016/0167-4838(86)90173-1. PMID   2423133.
• McNearney TA, Odell C, Holers VM, Spear PG, Atkinson JP (November 1987). "Herpes simplex virus glycoproteins gC-1 and gC-2 bind to the third component of complement and provide protection against complement-mediated neutralization of viral infectivity". The Journal of Experimental Medicine. 166 (5): 1525–1535. doi:10.1084/jem.166.5.1525. PMC   2189652 . PMID   2824652.
• Yang F, Naberhaus KH, Adrian GS, Gardella JM, Brissenden JE, Bowman BH (1987). "The vitamin D-binding protein gene contains conserved nucleotide sequences that respond to heavy metal, adipocyte and mitotic signals". Gene. 54 (2–3): 285–290. doi:10.1016/0378-1119(87)90499-9. PMID   2958390.
• Cooke NE, Willard HF, David EV, George DL (July 1986). "Direct regional assignment of the gene for vitamin D binding protein (Gc-globulin) to human chromosome 4q11-q13 and identification of an associated DNA polymorphism". Human Genetics. 73 (3): 225–229. doi:10.1007/BF00401232. PMID   3015768. S2CID   38816588.
• Nestler JE, McLeod JF, Kowalski MA, Strauss JF, Haddad JG (May 1987). "Detection of vitamin D binding protein on the surface of cytotrophoblasts isolated from human placentae". Endocrinology. 120 (5): 1996–2002. doi:10.1210/endo-120-5-1996. PMID   3552627.
• Pierce EA, Dame MC, Bouillon R, Van Baelen H, DeLuca HF (December 1985). "Monoclonal antibodies to human vitamin D-binding protein". Proceedings of the National Academy of Sciences of the United States of America. 82 (24): 8429–8433. Bibcode:1985PNAS...82.8429P. doi: 10.1073/pnas.82.24.8429 . PMC   390929 . PMID   3936035.
• Wooten MW, Nel AE, Goldschmidt-Clermont PJ, Galbraith RM, Wrenn RW (October 1985). "Identification of a major endogenous substrate for phospholipid/Ca2+-dependent kinase in pancreatic acini as Gc (vitamin D-binding protein)". FEBS Letters. 191 (1): 97–101. doi: 10.1016/0014-5793(85)81001-2 . PMID   4054306. S2CID   29613843.
• Constans J, Oksman F, Viau M (August 1981). "Binding of the apo and holo forms of the serum vitamin D-binding protein to human lymphocyte cytoplasm and membrane by indirect immunofluorescence". Immunology Letters. 3 (3): 159–162. doi:10.1016/0165-2478(81)90120-6. PMID   7026425.
• Braun A, Kofler A, Morawietz S, Cleve H (December 1993). "Sequence and organization of the human vitamin D-binding protein gene". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1216 (3): 385–394. doi:10.1016/0167-4781(93)90005-x. PMID   7505619.
• Swamy N, Roy A, Chang R, Brisson M, Ray R (April 1995). "Affinity purification of human plasma vitamin D-binding protein". Protein Expression and Purification. 6 (2): 185–188. doi: 10.1006/prep.1995.1023 . PMID   7606167.

External links

• Overview of all the structural information available in the PDB for UniProt : P02774 (Vitamin D-binding protein) at the PDBe-KB .