Vitamin D-binding protein

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.

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.

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

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.

Interactive pathway map

Production

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

Regulation

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

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. 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. 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.

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. They have been proposed to account for some of the differences in vitamin D status in different ethnic groups, and have been found to correlate with the response to vitamin D supplementation.

References

References

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2. "Entrez Gene: GC group-specific component (vitamin D binding protein)".
3. (2020). "Vitamin D Binding Protein: A Historic Overview". Frontiers in Endocrinology.
4. (February 2002). "A structural basis for the unique binding features of the human vitamin D-binding protein". Nature Structural Biology.
5. (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.
6. (June 1988). "Evidence of a novel association of unsaturated fatty acids with Gc (vitamin D-binding protein)". Biochemical and Biophysical Research Communications.
7. (1980). "Vitamin D-binding protein (Gc-globulin) binds actin.". Journal of Biological Chemistry.
8. (July 2006). "Gc-globulin: roles in response to injury". Clinical Chemistry.
9. (October 2015). "Behind the scenes of vitamin D binding protein: more than vitamin D binding". Best Practice & Research. Clinical Endocrinology & Metabolism.
10. (July 2008). "Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF". Translational Oncology.
11. (2019). "Vitamin D Binding Protein: A Historic Overview". Frontiers in Endocrinology.
12. (February 1992). "Characterization, primary structure, and evolution of lamprey plasma albumin". Protein Science.
13. (1976). "The plasma transport proteins of 25-hydroxycholecalciferol in fish, amphibians, reptiles and birds". Comparative Biochemistry and Physiology. B, Comparative Biochemistry.
14. (2022). "Evolutionary Transformations of Albumin Using the Example of Model Species of Jawless Agnatha and Bony Jawed Fish (Review)". Inland Water Biology.
15. (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.
16. (November 2013). "Vitamin D-binding protein and vitamin D status of black Americans and white Americans". The New England Journal of Medicine.
17. (January–February 2013). "Common variants of the vitamin D binding protein gene and adverse health outcomes". Critical Reviews in Clinical Laboratory Sciences.