Talk:Growth hormone-binding protein

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Growth hormone-binding protein (GHBP) is a soluble carrier protein for growth hormone (GH).

Translation/Formation of the Protein
The same gene that codes for growth hormone receptor (GHR) also codes for GHBP, as the extracellular domain of GHR is shed off in order to produce the carrier protein. This process is called “receptor ectodomain shedding.” In human, the genes that that encode for GHBP, are on chromosome 5, specifically within Exons 3 through 7, as well as a part of Exon 2. As the extracellular domain alone, the polypeptide consists of 246 amino acids and is water-soluble. The protein is roughly 60,000 kDA in size. In humans and rabbits, metzincin metalloproteinase membrane protein tumor-necrosis factor alpha converting enzyme (TACE) is postulated to play a significant role in this post-translational processing. TACE is activated by the protein kinase C pathway. Alternatively, in studied mice and rats, the extracellular domain is formed through alternative splicing of the primary GHR transcript. When the growth hormone (GH) is bound to dimerized GHR, the shedding activity is inhibited. GH is, however, necessary to be present in some concentration in the bloodstream for the extracellular domain of GHR to be cleaved.

Function
The physiological function of GHBP is not precisely known at this time. Assays estimate that growth hormone and growth hormone binding protein form a complex at a one-to-two ratio. There exists two isoforms of GHBP in the blood, one that binds GH with high affinity and the other binds with low affinity; yet it is believed that the circulating protein binds with higher affinity than the receptor regardless of which isoform. The isoforms vary based on whether or not they include amino acids encoded by Exon 3. Studies have shown that between the two variants, the GHBP with Exon 3 has a higher affinity for growth hormone than the protein missing Exon 3. Furthermore, the truncated version of GHR is shown to more frequently be shed into the soluble GHBP form than its fully translated counterpart. The clearance rate for GHBP alone is much faster than when it is bound to its ligand. Additionally, current literature has given evidence that the carrier protein prolongs the half-life of growth hormone through its binding, yet this could be confounded by the fact that binding prevents GH from binding to GHR. Growth hormone binding protein is present in much higher concentrations within the blood stream rather than in surrounding tissues. Studies show that GHBP regulates GHR transcription in rats. If there is low GHBP concentration then there is high levels of GHR expression. Conversely, high levels of GHBP protein show negative correlation with levels of growth hormone receptor expression. Growth hormone binding protein binds growth hormone by using the ligand’s C-terminal disulfide bridges. Two disulfide bridges link four-helix bundles and they make direct contact with the extracellular domain of the growth hormone receptor. This is the same mechanism by which GHBP binds GH. When the cysteine amino acids are mutated and the disulfide bridges are disrupted, the stability of the ligand to bind to the active site of the protein is significantly lessened.