Vitamin D-binding protein

Short description: Mammalian protein found in Homo sapiens

Generic protein structure example

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]

## Contents

* 1 Structure
* 2 Function
* 2.1 Interactive pathway map
* 3 Production
* 4 Regulation
* 5 Evolution
* 6 Variation
* 7 References
* 8 Further reading
* 9 External links

## 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]

Beyond acting as the carrier protein for vitamin D and its metabolites, DBP also transports free fatty acids,[6] binds to actin[7] and may help prevent actin polymerization during tissue injury.[8] It also might serve as a macrophage activator, contributing to the inflammatory response by modulating T-cell activity.[9]

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.[10]

### Interactive pathway map

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

[[File:

|{{{bSize}}}px|alt=Vitamin D Synthesis Pathway (view / edit)]]

Vitamin D Synthesis Pathway (view / edit)

1. ↑ The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531". http://www.wikipathways.org/index.php/Pathway:WP1531.

## 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.[11]

## 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.[12] 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.[13] 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.[14]

## Variation

Many genetic variants of the GC gene are known. They produce 6 main haplotypes and 3 main protein variants (Gc1S, Gc1F and Gc2).[15] The genetic variations are associated with differences in circulating 25-hydroxyvitamin D levels.[16] They have been proposed to account for some of the differences in vitamin D status in different ethnic groups,[17] and have been found to correlate with the response to vitamin D supplementation.[15]

## References

1. ↑ "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. doi:10.1159/000152857. PMID 558959.
2. ↑ 2.0 2.1 "Entrez Gene: GC group-specific component (vitamin D binding protein)". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=2638.
3. ↑ 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. PMID 31998239.
4. ↑ "A structural basis for the unique binding features of the human vitamin D-binding protein". Nature Structural Biology 9 (2): 131–6. February 2002. doi:10.1038/nsb754. PMID 11799400.
5. ↑ 5.0 5.1 "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. doi:10.1093/ajcn/88.2.491S. PMID 18689389.
6. ↑ Williams, Merfyn H.; Van Alstyne, Eldwin L.; Galbraith, Robert M. (1988). "Evidence of a novel association of unsaturated fatty acids with Gc (Vitamin D-binding protein)" (in en). Biochemical and Biophysical Research Communications 153 (3): 1019–1024. doi:10.1016/S0006-291X(88)81330-5. https://linkinghub.elsevier.com/retrieve/pii/S0006291X88813305.
7. ↑ Van Baelen, H.; Bouillon, R.; De Moor, P. (1980). "Vitamin D-binding protein (Gc-globulin) binds actin." (in en). Journal of Biological Chemistry 255 (6): 2270–2272. doi:10.1016/S0021-9258(19)85885-4. https://linkinghub.elsevier.com/retrieve/pii/S0021925819858854.
8. ↑ Meier, Ursula; Gressner, Olav; Lammert, Frank; Gressner, Axel M (2006-07-01). "Gc-Globulin: Roles in Response to Injury" (in en). Clinical Chemistry 52 (7): 1247–1253. doi:10.1373/clinchem.2005.065680. ISSN 0009-9147. https://academic.oup.com/clinchem/article/52/7/1247/5626860.
9. ↑ Delanghe, Joris R.; Speeckaert, Reinhart; Speeckaert, Marijn M. (2015). "Behind the scenes of vitamin D binding protein: More than vitamin D binding" (in en). Best Practice & Research Clinical Endocrinology & Metabolism 29 (5): 773–786. doi:10.1016/j.beem.2015.06.006. https://linkinghub.elsevier.com/retrieve/pii/S1521690X15000676.
10. ↑ "Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF" ([PDF]). Translational Oncology 1 (2): 65–72. July 2008. doi:10.1593/tlo.08106. PMID 18633461. PMC 2510818. http://www.transonc.com/pdf/manuscript/v01i02/neo08106.pdf.
11. ↑ "Vitamin D Binding Protein: A Historic Overview". Frontiers in Endocrinology 10: 910. 2019. doi:10.3389/fendo.2019.00910. PMID 31998239.
12. ↑ Gray, Jeffrey E.; Doolittle, Russell F. (1992). "Characterization, primary structure, and evolution of lamprey plasma albumin" (in en). Protein Science 1 (2): 289–302. doi:10.1002/pro.5560010211. ISSN 0961-8368. PMID 1304910. PMC 2142188. https://onlinelibrary.wiley.com/doi/10.1002/pro.5560010211.
13. ↑ Hay, A.W.M.; Watson, G. (1976). "The plasma transport proteins of 25-hydroxycholecalciferol in fish, amphibians, reptiles and birds" (in en). Comparative Biochemistry and Physiology Part B: Comparative Biochemistry 53 (2): 167–172. doi:10.1016/0305-0491(76)90029-8. https://linkinghub.elsevier.com/retrieve/pii/0305049176900298.
14. ↑ Andreeva, A. M. (2022). "Evolutionary Transformations of Albumin Using the Example of Model Species of Jawless Agnatha and Bony Jawed Fish (Review)" (in en). Inland Water Biology 15 (5): 641–658. doi:10.1134/S1995082922050029. ISSN 1995-0829. https://link.springer.com/10.1134/S1995082922050029.
15. ↑ 15.0 15.1 "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. doi:10.3109/10408363.2012.750262. PMID 23427793.
16. ↑ "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. doi:10.1016/j.jsbmb.2010.03.073. PMID 20363324.
17. ↑ "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. doi:10.1056/NEJMoa1306357. PMID 24256378.

## Further reading

* "Molecular basis for the three major forms of human serum vitamin D binding protein (group-specific component)". Biochemistry 18 (8): 1611–7. April 1979. doi:10.1021/bi00575a036. PMID 218624.
* "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. doi:10.1007/BF00194311. PMID 1352271.
* "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. doi:10.1016/S0021-9258(19)50216-2. PMID 1374401.
* "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. doi:10.1016/0888-7543(92)90245-N. PMID 1535333.
* "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". The Journal of Infection 24 (3): 317–20. May 1992. doi:10.1016/S0163-4453(05)80037-4. PMID 1602151.
* "Mapping and conservation of the group-specific component gene in mouse". Genomics 7 (4): 509–16. August 1990. doi:10.1016/0888-7543(90)90193-X. PMID 1696927.
* "Evolutionary and structural relationships among the group-specific component, albumin and alpha-fetoprotein". Nucleic Acids Research 13 (22): 8007–17. November 1985. doi:10.1093/nar/13.22.8007. PMID 2415926.
* "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. doi:10.1073/pnas.82.23.7994. PMID 2415977. Bibcode: 1985PNAS...82.7994Y.
* "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. doi:10.1172/JCI112256. PMID 2416779.
* "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. doi:10.1016/0167-4838(86)90173-1. PMID 2423133.
* "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. doi:10.1084/jem.166.5.1525. PMID 2824652.
* "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. doi:10.1016/0378-1119(87)90499-9. PMID 2958390.
* "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. doi:10.1007/BF00401232. PMID 3015768.
* "Detection of vitamin D binding protein on the surface of cytotrophoblasts isolated from human placentae". Endocrinology 120 (5): 1996–2002. May 1987. doi:10.1210/endo-120-5-1996. PMID 3552627.
* "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. doi:10.1073/pnas.82.24.8429. PMID 3936035. Bibcode: 1985PNAS...82.8429P.
* "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. doi:10.1016/0014-5793(85)81001-2. PMID 4054306.
* "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. doi:10.1016/0165-2478(81)90120-6. PMID 7026425.
* "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. doi:10.1016/0167-4781(93)90005-x. PMID 7505619.
* "Affinity purification of human plasma vitamin D-binding protein". Protein Expression and Purification 6 (2): 185–8. April 1995. 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.

* v
* t
* e

PDB gallery

* 1j78: Crystallographic analysis of the human vitamin D binding protein

* 1j7e: A Structural Basis for the Unique Binding Features of the Human Vitamin D-binding Protein

* 1kw2: CRYSTAL STRUCTURE OF UNCOMPLEXED VITAMIN D-BINDING PROTEIN

* 1kxp: CRYSTAL STRUCTURE OF HUMAN VITAMIN D-BINDING PROTEIN IN COMPLEX WITH SKELETAL ACTIN

* 1lot: CRYSTAL STRUCTURE OF THE COMPLEX OF ACTIN WITH VITAMIN D-BINDING PROTEIN

* 1ma9: Crystal structure of the complex of human vitamin D binding protein and rabbit muscle actin

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