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Vitamin D-binding protein

From Wikipedia, the free encyclopedia
(Redirected from GC (gene))

GC
Identifiers
AliasesGC, DBP, DBP/GRD3, HEL-S-51, VDBG, VDBP, Gc-MAF, GcMAF, vitamin D binding protein, DBP-maf, VDB, GC vitamin D binding protein
External IDsOMIM: 139200; MGI: 95669; GeneCards: GC
Available structures
PDBOrtholog search: PDBe RCSB
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
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 MbChr 5: 89.57 – 89.61 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

GC Vitamin D binding protein,[5] also referred to as Vitamin D binding protein (DBP), is a protein that is encoded by the GC gene in Homo sapiens (modern humans).[5][6][7] DBP is genetically the oldest member of the albuminoid family and appeared early in the evolution of vertebrates.[8]

Structure

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Human GC is a glycosylated alpha-globulin, 52.92 kDa in size.[9][10] Its 474 amino acids are encoded by a sequence of 1685 nucleotides (including the nucleotides preceding the protein-coding section, composed of the 5' UTR and 3' UTR) located at 4q13.3.[5][11] 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.[12]

Function

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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 (CSF), and on the surface of many cell types.[5]

It binds to 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).[5] The major proportion of vitamin D in blood is bound to this protein. Once bound, it transports vitamin D and its plasma metabolites between the skin, liver, and kidney, and then on to the various target tissues.[5][7][13] The expression of GC, and therefore the production of GC Vitamin D binding protein, is restricted towards the liver; in an RNA-sequence (RNA-seq) study of tissues samples from 95 human individuals across 27 tissue representations analysed on December 19, 2024, GC was expressed primarily in the tissue of the liver, at a mean RPKM (reads per kilobase million) value of 1258.79 ± 214.721 across 3 samples.[5][14] In comparison, the next highest RPKM means were in the anatomically nearby gallbladder, at a value of 235.12 ± 73.639 across 3 samples, followed by the stomach, at a value of 23.974 ± 19.053 across 3 samples, the duodenum, at a value of 22.508 ± 6.514 across 2 samples, and the kidney, at a value of 12.033 ± 12.168 across 4 samples.[5] Other tissue samples held a negligible value in comparison to the liver, gallbladder, stomach, duodenum, and kidney.[5]

Beyond acting as the carrier protein for vitamin D and its metabolites, DBP also transports free fatty acids,[15] binds to actin[16] and may help prevent actin polymerization during tissue injury.[17] It also might serve as a macrophage activator, contributing to the inflammatory response by modulating T-cell activity.[18]

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.[19]

Production

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It is synthesized by hepatic parenchymal cells and secreted into the blood circulation.[13]

Regulation

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The transcription factor HFN1α is a positive regulator while HFN1β is a dominant negative regulator of DBP expression.[20]

Evolution

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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.[21] 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.[22] 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.[23]

Variation

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Many genetic variants of the GC gene are known. They produce 6 main haplotypes and 3 main protein variants (Gc1S, Gc1F and Gc2).[24] The genetic variations are associated with differences in circulating 25-hydroxyvitamin D levels.[25] They have been proposed to account for some of the differences in vitamin D status in different ethnic groups,[26] and have been found to correlate with the response to vitamin D supplementation.[24]

References

[edit]
Photochemical synthesis of vitamin D3 (cholecalciferol, D3) occurs cutaneously where pro-vitamin D3 (7-dehydrocholesterol) is converted to pre-vitamin D3 (pre-D3) in response to ultraviolet B (sunlight) exposure. DHCR7 encodes the enzyme 7-dehydrocholesterol (7-DHC) reductase, which converts 7-DHC to cholesterol, thereby removing the substrate from the synthetic pathway of vitamin D3, a precursor of 25-hydroxyvitamin D3.The finding that common variants at DHCR7 are strongly associated with circulating 25-hydroxyvitamin D concentrations suggests that this enzyme could have a larger role in regulation of vitamin D status than has previously been recognised. Vitamin D3, obtained from the isomerization of pre-vitamin D3 in the epidermal basal layers or intestinal absorption of natural and fortified foods and supplements, binds to vitamin D-binding protein (DBP) in the bloodstream, and is transported to the liver. D3 is hydroxylated by liver 25-hydroxylases (25-OHase). The resultant 25-hydroxycholecalciferol (25(OH)D3) is 1-hydroxylated in the kidney by 25-hydroxyvitamin D3-1 -hydroxylase (1-OHase). This yields the active secosteroid 1 ,25(OH)2D3 (calcitriol), which has different effects on various target tissues. The synthesis of 1,25(OH)2D3 from 25(OH)D3 is stimulated by parathyroid hormone (PTH) and suppressed by Ca2+, Pi and 1,25(OH)2D3 itself. The rate-limiting step in catabolism is the degradation of 25(OH)D3 and 1,25(OH)2D3 to 24,25(OH)D3 and 1,24,25(OH)2D3, respectively,which occurs through 24-hydroxylation by 25-hydroxyvitamin D 24-hydroxylase (24-OHase), encoded by the CYP24A1 gene. 24,25(OH)D3 and 1,24,25(OH)2D3 are consequently excreted. Vitamin D activity is mediated through binding of 1,25(OH)2D3 to the vitamin D receptor (VDR), which can regulate transcription of other genes involved in cell regulation, growth, and immunity. VDR modulates the expression of genes by forming a heterodimer complex with retinoid-X-receptors (RXR). (Taken from the following article: https://www.wikipathways.org/pathways/WP1531.html)
Vitamin D metabolism (WP1531) - Homo sapiens (modern human). WikiPathways has become read-only and the Classic site has been retired as of May 1, 2026.[27]
  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000145321 – Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 4 5 6 7 8 9 "GC vitamin D binding protein". NCBI. Retrieved 2026-06-14.
  6. ↑ 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.
  7. 1 2 "Entrez Gene: GC group-specific component (vitamin D binding protein)".
  8. ↑ 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.
  9. ↑ "Protein Molecular Weight Calculator". www.sciencegateway.org. Retrieved 2026-06-14.
  10. ↑ "RecName: Full=Vitamin D-binding protein; Short=DBP; Short=VDB; AltName - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2026-06-14.
  11. ↑ "Homo sapiens GC vitamin D binding protein (GC), transcript variant 1, mRNA". National Center for Biotechnology Information. April 28, 2025.
  12. ↑ 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.
  13. 1 2 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.
  14. ↑ "BTEP: What is the difference between RPKM, FPKM and TPM". 2020-04-02. Retrieved 2026-06-14.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. 1 2 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ "Home | WikiPathways". www.wikipathways.org. Retrieved 2026-06-14.

Further reading

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