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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

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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.[1] This process is called “receptor ectodomain shedding.” [2] 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.[3] The protein is roughly 60,000 kDA in size.[4] 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.[5] 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. [6]

References

  1. ^ Leung DW, Spencer SA, Cachianes G, et al. 1987 Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature. 330:537–543
  2. ^ Alele J, Jiang J, Goldsmith JF, et al. 1998 Blockade of growth hormone receptor shedding by a metalloprotease inhibitor. Endocrinology. 139:1927–1935.
  3. ^ Schilbach K, Bidlingmaier M. Growth hormone binding protein - physiological and analytical aspects. Best Pract Res Clin Endocrinol Metab. 2015;29(5):671-83.
  4. ^ Fisker S. Physiology and pathophysiology of growth hormone-binding protein: methodological and clinical aspects. Growth Horm IGF Res. 2006;16(1):1-28.
  5. ^ Roy A, Black CT, Rauch CJ, et al. 1997 A metalloproteinase disintegrin that releases tumor-necrosis factor-α from cells. Nature. 385:729–733
  6. ^ Waters MJ. The growth hormone receptor. Growth Horm IGF Res. 2015;

Function

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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.[1] 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.[2][3][4] 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. [5] 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. [6] 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. [7]

References

  1. ^ Junnila RK, Wu Z, Strasburger CJ. The role of human growth hormone's C-terminal disulfide bridge. Growth Horm IGF Res. 2013;23(3):62-7.
  2. ^ Amit, Tamar, Moussa B.H. Youdim, and Ze've Hochberg. "Does Serum Growth Hormone (GH) Binding Protein Reflect Human GH Receptor Function?" Journal of Clinical Endocrinology & Metabolism 85.3 (1999). Endocrine Society. Web.
  3. ^ Iida K, Takahashi Y, Kaji H, et al. 1998 Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. J Clin Endocrinol Metab. 83:531–537
  4. ^ Dastot F, Sobrier M-L, Duquesnoy P, Duriez B, Goossens M, Amselem S. 1996 Alternatively spliced forms in the cytoplasmic domain of the human growth hormone (GH) receptor regulate its ability to generate a soluble GH-binding protein. Proc Natl Acad Sci USA. 93:10723–10728
  5. ^ Benard, R., and M. J. Waters. "The Serum Growth Hormone Binding Protein: Pregnant with Possibilities." Journal for Endocrinology 14th ser. 153.1 (1997). Journal for Endocrinology.
  6. ^ H. Maheshwari, S. Lillioja, C.E. Castillo, M. Mercado, G. Baumann, Growth hormone-binding protein in human lymph, J. Clin. Endocrinol. Metab. 80 (1995) 3582–3584.
  7. ^ Junnila RK, Wu Z, Strasburger CJ. The role of human growth hormone's C-terminal disulfide bridge. Growth Horm IGF Res. 2013;23(3):62-7
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