Best Practice & Research Clinical Endocrinology & Metabolism
10Behind the scenes of vitamin D binding protein: More than vitamin D binding
Introduction
Vitamin D binding protein (DBP) is a sparsely glycosylated (0.5–1%) alpha2-globulin with a molecular weight of 52–59 kDa [1], ∗[2], ∗[3]. Being a member of the multigene cluster that includes albumin (ALB), α-fetoprotein (AFP), and α-albumin/afamin (AFM), the human DBP gene is localized at 4q11-q13 on the long arm of chromosome 4 [1], ∗[2]. All four genes show a predominantly hepatic expression with overlapping developmental profiles [2]. They share a homologous three-domain structure, defined by the invariant positions of cysteine and the nearly identical disulfide bridge patterns [4], and have a conserved position of introns within the coding region [5]. The DBP gene is the most divergent member of the albuminoid superfamily, which probably arose by the triplication of the ancestral gene with a 192 amino acid sequence [6]. This gene is separated by at least 1500 kb from the other 3 genes and is composed of 458 amino acids. It lies in a head-to-head configuration with and has an inverted transcriptional orientation as ALB/AFP/AFM [2]. The general characteristics of DBP are summarized in Table 1.
The 3 major circulating DBP alleles (DBP1F, DBP1S, DBP2) are defined by the genetic polymorphisms rs7041 and rs4588 [7]. DBP1 and DBP2 differ from each other by four amino acids (152 Gly → Glu, 311 Glu → Arg, 416 Asp → Glu and 420 Arg → Thr) and by the attached carbohydrates [8]. DBP1F and DBP1S have an identical primary structure, except at position 416, where aspartic acid is substituted by glutamic acid. The partial glycosylation of DBP1S comprises a linear O-linked trisaccharide of the type GalNAc-Gal-Sia attached to the threonine residue at position 420 ∗[3], [9]. Besides the three common alleles, a large number (>120) of unique racial variants [10] and single nucleotide polymorphisms (SNPs) of DBP have been described [11]. The geographical variation in the DBP allele frequencies is associated with skin pigmentation and relative sun light exposure. Populations with a pale skin are characterized by a relatively lower frequency of the DBP1F allele and a higher frequency (50–60%) of the DBP1S allele. The DBP1F allele frequency is high among populations of African ancestry, whereas Caucasians have a markedly higher DBP2 allele frequency [12].
DBP is composed of three structurally similar domains with a C-terminal truncation of the third repeat. The first domain has the characteristic α-helical arrangement, which allows for binding of vitamin D3 ligands. The vitamin D binding site is composed of hydrophobic residues of helices 1–6 (amino acids 35–49). This binding site at the N-terminus of DBP is a cleft located at the surface of DBP, whereas the vitamin D binding site of the vitamin D receptor is a closed pocket in the inner structure of the receptor. The second domain is similar, but a coil folding has replaced helix 7 and in the third domain only helices 1–4 are present [13]. The acting binding site is located between amino acids 373–403, spanning parts of domains 2 and 3 [14], whereas also a part of domain 1 interacts with actin [15]. Finally, C5a/C5a des Arg binding (amino acids 126–175) and plasma membrane binding domains (amino acids 150–172 and amino acids 379–402) have been identified [16].
Diverse physiologically important properties have been attributed to DBP (Fig. 1). First of all, circulating vitamin D metabolites are mainly transported bound to DBP and albumin is the major secondary carrier, especially in patients with a low serum DBP concentration [17]. However, as only 1–2% of its sterol binding sites are utilized, multiple additional metabolic roles beyond vitamin D transport have been described for DBP: actin scavenging, modulation of inflammatory processes and innate immunity, binding of fatty acids and influencing bone metabolism. As we described already the interesting relationship between DBP polymorphisms and susceptibility to diseases [18], the purpose of this review was to give an overview of the current knowledge and evidence of the fundamental biological functions of DBP, illustrated by some examples in human pathologies.
Section snippets
Analytical aspects and clinical significance of vitamin D binding protein
The presence of DBP has been demonstrated in serum, urine, breast milk, ascitic fluid, cerebrospinal fluid, saliva, seminal fluid and on the surfaces of lymphocytes, neutrophils and monocytes. Differential mRNA expression has been reported in brain, heart, lungs, kidneys, placenta, spleen, testes and uterus ∗[19], [20]. The estrogen dependent synthesis of DBP is fulfilled by the hepatocytes. In comparison with blood, where the highest concentration of DBP is found, lower expression levels have
Vitamin D binding protein: what's in a name?
As the main function of the initially unnamed serum protein, referred as group-specific component of serum (Gc-globulin), was binding, solubilization and transport of vitamin D and its metabolites, the name was changed into DBP. In comparison with vitamin D metabolites, the serum concentration of DBP is 20-fold higher, which results in a 5% occupation of the binding sites on DBP by vitamin D sterols [50]. This large molar excess of DBP has probably several potential roles: (1) protection
The role of vitamin D binding protein in the extracellular actin scavenger system
Being the most abundant and highly conserved protein inside all eukaryotic cells, large quantities of actin are released into the circulation during extensive tissue damage and cell death. Besides monomeric globular actin (G-actin), extacellular polymerized filamentous actin (F-actin) is formed in association with coagulation factor Va, triggering disseminated intravascular coagulation and multiple organ dysfunction syndrome [71]. To counteract these procoagulant effects, the intravascular
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