As well as binding sex steroids, brand new SHBG homodimer by itself serves as a great ligand having a particular, high affinity receptor (R
When you look at the people, for every SHBG monomer subunit includes a 373 amino acidic polypeptide having three oligosaccharide front side chains and two disulfide ties (2). Each SHBG subunit include a good steroid binding website effective at joining DHT, testosterone, otherwise estradiol, in a fashion that the brand new adult SHBG homodimer provides a couple of distinctive line of steroid joining sites (29). More over, for every monomer include a few ?-sheet sets which can be important in the brand new dimerization of the adult SHBG glycoprotein. Especially, 7 hydrogen ties try shaped along the screen of ?-sheet sets in a manner that two continuous 14-stuck ?-sheet sets try formed throughout the mature homodimer (29;30).
Just like other steroid hormones-binding glycoproteins eg cortisol-joining globulin otherwise thyroxine-binding globulin, adult SHBG includes oligosaccharide side stores, in addition to architectural providers of your own carbohydrate moieties are certain so you can each joining glycoprotein (31). Particularly, for every single subunit of the SHBG homodimer is actually described as about three oligosaccharide moieties, a keen O-connected glycosylation site at the Thr7, and Letter-connected web sites from the Asn 351 and you can Asn 367 (32–34). As the oligosaccharide top-organizations towards SHBG do not seem to be crucial for this new glycoprotein’s steroid-binding activity (34), just like the biologic mode present in other glycoproteins, SHBG glycosylation could be important in the glycoprotein’s correspondence with certain cell-surface receptors (35).
SHBG) present on the plasma membranes of target cells (8;10;11;36;37). Only steroid-free SHBG appears to bind to RSHBG; however, once SHBG is bound to the receptor, sex steroids can then activate the anchored SHBG-RSHBG complex (8). Moreover, adding additional complexity to the system, not all steroids that bind to the SHBG-RSHBG complex function as agonists; some are antagonists (8). Moreover, some steroids such as DHT may function as either an agonist or antagonist for the system, depending on the specific target cell type (8;38). Although the full downstream effects of SHBG-RSHBG complex activation remain unclear, complex activation appears to affect target cell growth in addition to modulating the transcriptional activity of classic intracellular steroid hormone receptors (8).
SHBG may also actively participate in the uptake of sex steroids by target tissues through interactions with megalin, an endocytic receptor distinct from RSHBG (9). Although the uptake of SHBG-bound sex hormones via the megalin-mediated pathway together2night is controversial (39), such findings support an expanded role of SHBG in sex steroids physiology.
SHBG Gene Structure and you will Splice Alternatives
The SHBG gene, located on the chromosome 17p12>p13, consists of eight exons separated by seven small introns (2;40;41). Exon 1 encodes for the nacent protein’s 29 amino acid secretion signal polypeptide (2), while the remaining exons [2–8] encode two contiguous laminin G–like (LG) domains (41). The amino-terminal LG domain encoded by exons 2–4 contains the steroid-binding site, the dimer interface, and several cation-binding sites (42). A ten amino acid sequence (residues 48–57) within exon 3 appears to correspond to the RSHBG-binding domain (43).
Although hepatocytes are the primary source of plasma SHBG (44), extrahepatic tissues, including testis, prostate, ovary, endometrium, breast, placenta and hypothalamus also express SHBG mRNA in humans (45–51). In fact, recent evidence suggests that the transcriptional control of SHBG gene expression is extremely complex and is regulated by at least three distinct promoters (PL, PT, and PN) which are expressed differentially in various human tissues (52).
Activation of the downstream promoter (PL), results in the production of the most common SHBG mRNA transcript [exon1L-8] (52). The exon IL-8 transcript is predominantly expressed in hepatocytes and encodes for all eight exons present in the SHBG gene. PL activation in the testis results in an identical eight-exon mRNA; however, distinct post-translational processing of the testicular transcript results in the production of androgen binding protein (ABP) instead of mature SHBG (45;53). In addition to the liver and testis, the 1L-8 mRNA transcript is also expressed in the human prostate, breast and regions of the brain (52). In the testis, activation of a second SHBG promoter (PT), located 1.9 kb upstream of PL, produces a second major mRNA transcript (45;52). In addition to possessing an unique 5? end amino acid sequence (exon 1T), the second testicular transcript also lacks exon 7(45;52). Recently, Nakhla and colleagues described a third SHBG gene promoter (PN), located within intron 1 of the adjacent FXR2 gene (52). Similar to PL and PT transcripts, PN transcripts possess a distinct first exon (1N). Differential activation of the three promoters triggers alternative splicing of SHBG exons which, in turn, may result in the expression of at least 19 unique SHBG transcripts (52). Furthermore, the pattern of SHBG transcript expression differs in normal tissues with PL-, PT-, and PN– derived transcripts being most abundantly expressed in the liver, testis, and prostate, respectively (52). Interestingly, alternative splicing of SHBG is more pronounced in certain cancer cell lines compared with normal tissues (52) ( Figure 1 ). Although Nakhla and colleagues hypothesize that only certain PL-derived transcripts produce stable SHBG isoforms, the potential biologic significance of alternatively spliced SHBG gene transcripts remains unclear (52).