Vitamin D-binding protein (DBP), also/originally known asgc-globulin (group-specificcomponent), is aprotein that in humans is encoded by theGCgene.[5][6] DBP is genetically the oldest member of thealbuminoid family and appeared early in the evolution of vertebrates.[7]
Human GC is a glycosylatedalpha-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]
It is able to bind the various forms ofvitamin D includingergocalciferol (vitamin D2) andcholecalciferol (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 transportsfree fatty acids,[10] binds toactin[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]
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]
Many genetic variants of theGC gene are known. They produce 6 mainhaplotypes 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]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^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):105–7.doi:10.1159/000152857.PMID558959.
^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):131–6.doi:10.1038/nsb754.PMID11799400.S2CID38990672.
^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):471–7.doi:10.1016/j.jsbmb.2010.03.073.PMID20363324.S2CID20057294.
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):1611–7.doi:10.1021/bi00575a036.PMID218624.
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):401–6.doi:10.1007/BF00194311.PMID1352271.S2CID1913655.
Szpirer C, Riviere M, Cortese R, Nakamura T, Islam MQ, Levan G, Szpirer J (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.PMID1535333.
Dawson SJ, White LA (May 1992). "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin".The Journal of Infection.24 (3):317–20.doi:10.1016/S0163-4453(05)80037-4.PMID1602151.
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):509–16.doi:10.1016/0888-7543(90)90193-X.PMID1696927.
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):189–98.doi:10.1016/0167-4838(86)90173-1.PMID2423133.
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):285–90.doi:10.1016/0378-1119(87)90499-9.PMID2958390.
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):225–9.doi:10.1007/BF00401232.PMID3015768.S2CID38816588.
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.PMID3552627.
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):159–62.doi:10.1016/0165-2478(81)90120-6.PMID7026425.
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):385–94.doi:10.1016/0167-4781(93)90005-x.PMID7505619.
