Vitamin D-binding protein explained

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.^{[1] [2]} DBP is genetically the oldest member of the albuminoid family and appeared early in the evolution of vertebrates.^[3]

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.^[4]

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.^{[2] [5]}

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.^[6]

Interactive pathway map

Production

It is synthesized by hepatic parenchymal cells and secreted into the blood circulation.^[5]

Regulation

The transcription factors HFN1α is a positive regulator while HFN1β is a dominant negative regulator of DBP expression.^[7]

Variation

Many genetic variants of the GC gene are known. They produce 6 main haplotypes and 3 main protein variants (Gc1S, Gc1F and Gc2). The genetic variations are associated with differences in circulating 25-hydroxyvitamin D levels.^[8] They have been proposed to account for some of the differences in vitamin D status in different ethnic groups,^[9] and have been found to correlate with the response to vitamin D supplementation.^[10]

Further reading

• Svasti J, Kurosky A, Bennett A, Bowman BH . Molecular basis for the three major forms of human serum vitamin D binding protein (group-specific component) . Biochemistry . 18 . 8 . 1611–7 . April 1979 . 218624 . 10.1021/bi00575a036 .
• Braun A, Bichlmaier R, Cleve H . 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 . 401–6 . June 1992 . 1352271 . 10.1007/BF00194311 . 1913655 .
• Esteban C, Geuskens M, Ena JM, Mishal Z, Macho A, Torres JM, Uriel J . Receptor-mediated uptake and processing of vitamin D-binding protein in human B-lymphoid cells . The Journal of Biological Chemistry . 267 . 14 . 10177–83 . May 1992 . 10.1016/S0021-9258(19)50216-2 . 1374401 . free .
• Szpirer C, Riviere M, Cortese R, Nakamura T, Islam MQ, Levan G, Szpirer J . 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 . June 1992 . 1535333 . 10.1016/0888-7543(92)90245-N .
• Dawson SJ, White LA . Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin . The Journal of Infection . 24 . 3 . 317–20 . May 1992 . 1602151 . 10.1016/S0163-4453(05)80037-4 .
• Yang F, Bergeron JM, Linehan LA, Lalley PA, Sakaguchi AY, Bowman BH . Mapping and conservation of the group-specific component gene in mouse . Genomics . 7 . 4 . 509–16 . August 1990 . 1696927 . 10.1016/0888-7543(90)90193-X .
• Yang F, Luna VJ, McAnelly RD, Naberhaus KH, Cupples RL, Bowman BH . Evolutionary and structural relationships among the group-specific component, albumin and alpha-fetoprotein . Nucleic Acids Research . 13 . 22 . 8007–17 . November 1985 . 2415926 . 322106 . 10.1093/nar/13.22.8007 .
• Yang F, Brune JL, Naylor SL, Cupples RL, Naberhaus KH, Bowman BH . 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 . 7994–8 . December 1985 . 2415977 . 391428 . 10.1073/pnas.82.23.7994 . 1985PNAS...82.7994Y . free .
• Cooke NE, David EV . Serum vitamin D-binding protein is a third member of the albumin and alpha fetoprotein gene family . The Journal of Clinical Investigation . 76 . 6 . 2420–4 . December 1985 . 2416779 . 424397 . 10.1172/JCI112256 .
• Schoentgen F, Metz-Boutigue MH, Jollès J, Constans J, Jollès P . 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 . 189–98 . June 1986 . 2423133 . 10.1016/0167-4838(86)90173-1 .
• McNearney TA, Odell C, Holers VM, Spear PG, Atkinson JP . 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 . 1525–35 . November 1987 . 2824652 . 2189652 . 10.1084/jem.166.5.1525 .
• Yang F, Naberhaus KH, Adrian GS, Gardella JM, Brissenden JE, Bowman BH . The vitamin D-binding protein gene contains conserved nucleotide sequences that respond to heavy metal, adipocyte and mitotic signals . Gene . 54 . 2–3 . 285–90 . 1987 . 2958390 . 10.1016/0378-1119(87)90499-9 .
• Cooke NE, Willard HF, David EV, George DL . 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 . 225–9 . July 1986 . 3015768 . 10.1007/BF00401232 . 38816588 .
• Nestler JE, McLeod JF, Kowalski MA, Strauss JF, Haddad JG . Detection of vitamin D binding protein on the surface of cytotrophoblasts isolated from human placentae . Endocrinology . 120 . 5 . 1996–2002 . May 1987 . 3552627 . 10.1210/endo-120-5-1996 .
• Pierce EA, Dame MC, Bouillon R, Van Baelen H, DeLuca HF . Monoclonal antibodies to human vitamin D-binding protein . Proceedings of the National Academy of Sciences of the United States of America . 82 . 24 . 8429–33 . December 1985 . 3936035 . 390929 . 10.1073/pnas.82.24.8429 . 1985PNAS...82.8429P . free .
• Wooten MW, Nel AE, Goldschmidt-Clermont PJ, Galbraith RM, Wrenn RW . 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 . October 1985 . 4054306 . 10.1016/0014-5793(85)81001-2 . 29613843 . free .
• Constans J, Oksman F, Viau M . 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 . 159–62 . August 1981 . 7026425 . 10.1016/0165-2478(81)90120-6 .
• Braun A, Kofler A, Morawietz S, Cleve H . Sequence and organization of the human vitamin D-binding protein gene . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1216 . 3 . 385–94 . December 1993 . 7505619 . 10.1016/0167-4781(93)90005-x .
• Swamy N, Roy A, Chang R, Brisson M, Ray R . Affinity purification of human plasma vitamin D-binding protein . Protein Expression and Purification . 6 . 2 . 185–8 . April 1995 . 7606167 . 10.1006/prep.1995.1023 . free .

Notes and References

1. Mikkelsen M, Jacobsen P, Henningsen K . 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 . 105–7 . Jul 1977 . 558959 . 10.1159/000152857 .
2. Web site: Entrez Gene: GC group-specific component (vitamin D binding protein).
3. 6965021 . 2020 . Bouillon . R. . Schuit . F. . Antonio . L. . Rastinejad . F. . Vitamin D Binding Protein: A Historic Overview . Frontiers in Endocrinology . 10 . 910 . 10.3389/fendo.2019.00910 . 31998239 . free .
4. Verboven C, Rabijns A, De Maeyer M, Van Baelen H, Bouillon R, De Ranter C . A structural basis for the unique binding features of the human vitamin D-binding protein . Nature Structural Biology . 9 . 2 . 131–6 . February 2002 . 11799400 . 10.1038/nsb754 . 38990672 .
5. Norman AW . 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 . August 2008 . 18689389 . 10.1093/ajcn/88.2.491S. free .
6. Yamamoto N, Suyama H, Yamamoto N . Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF . Translational Oncology . 1 . 2 . 65–72 . July 2008 . 18633461 . 2510818 . [PDF] . 10.1593/tlo.08106.
7. Bouillon R, Schuit F, Antonio L, Rastinejad F . Vitamin D Binding Protein: A Historic Overview . Frontiers in Endocrinology . 10 . 910 . 2019 . 31998239 . 6965021 . 10.3389/fendo.2019.00910 . free .
8. McGrath JJ, Saha S, Burne TH, Eyles DW . 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 . 471–7 . July 2010 . 20363324 . 10.1016/j.jsbmb.2010.03.073 . 20057294 .
9. Powe CE, Evans MK, Wenger J, Zonderman AB, Berg AH, Nalls M, Tamez H, Zhang D, Bhan I, Karumanchi SA, Powe NR, Thadhani R . Vitamin D-binding protein and vitamin D status of black Americans and white Americans . The New England Journal of Medicine . 369 . 21 . 1991–2000 . November 2013 . 24256378 . 10.1056/NEJMoa1306357 . 4030388.
10. Malik S, Fu L, Juras DJ, Karmali M, Wong BY, Gozdzik A, Cole DE . Common variants of the vitamin D binding protein gene and adverse health outcomes . Critical Reviews in Clinical Laboratory Sciences . 50 . 1 . 1–22 . January–February 2013 . 23427793 . 3613945 . 10.3109/10408363.2012.750262 .