Abstract
A novel variant of chicken growth hormone (cGH) that is severely truncated has recently been discovered in the neural retina. It is, however, unknown whether this protein binds to GH receptors (GHRs) and has biological activity. This possibility has therefore been addressed by homology modeling, using human (h)GH as a template because it is the only GH molecule with a crystal structure and because hGH binds to cGH receptors (cGHRs). Most of the residues of the small (s)cGH model fitted the hGH template, apart from two restricted regions from Ser 12 to Gln 20 and from Ser 55 to Val 58. The scGH model differs, however, from hGH in structure: hGH is composed of a four-helix bundle, whereas scGH has three main helices. Helices 2, 3, and 4 of hGH correspond to helices 1, 2, and 3 of scGH, but they are longer by one, four, and one residues, respectively. The secondary structure of the C-terminus of scGH is therefore similar to C-terminal hGH. The N-terminus of scGH is, however, severely truncated, lacking the residues of the full-length molecule derived from exons 1, 2, and 3. The N-terminus of scGH also includes 20 residues derived from intron C of full-length cGH. The predicted structure of its N-terminus has no classical secondary structure (α-helix or β-sheet), whereas the N-terminus of hGH is composed of helix 1 and two mini-helices located between helix 1 and 2. This difference in ribbon structure results in a difference in the overall shape of the scGH model and hGH.
The possibility that scGH could bind to a GHR dimer was assessed by examining the primary and hypothetical tertiary structure of scGH. hGH binds the extracellular domain (ECD) of two GHRs sequentially at its binding site 1 (or high affinity site) then at its binding site 2 (or low affinity site). Sequence alignment of scGH with hGH demonstrates that scGH lacks three key residues (of 14) at site 1 and nine residues (of 15) at site 2. It is therefore unlikely that tight binding of ECD1 to the site 1 of scGH could occur. ScGH also lacks most of the site 2 residues, suggesting that it is unlikely that ECD2 would bind to the scGH model. In summary, we have developed a novel, structural model of scGH, with implications for its putative actions through classical GHRs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baudet M.L., Sanders E.J., and Harvey S. (2005) Small growth hormone variant (scGH) in the early chick embryo. Proc. 87th Ann. Meet. Endocr. Soc., San Diego, CA: P1–73.
Baudet M. L., Sanders E. J., and Harvey S. (2003) Retinal growth hormone in the chick embryo. Endocrinology 144, 5459–5468.
Bernat B., Pal G., Sun M., and Kossiakoff A.A. (2003) Determination of the energetics governing the regulatory step in growth hormone-induced receptor homodimerization. Proc. Natl. Acad. Sci. U. S. A. 100, 952–957.
Bonifacino J. S., Roguin L. P., and Paladini A. C. (1983) Formation of complexes between 125I-labelled human or bovine somatotropins and binding proteins in vivo in rat liver and kidney. Biochem J. 214, 121–132.
Casanueva F. F. (1992) Physiology of growth hormone secretion and action. Endocrinol. Metabol. Clinics N. Am. 21, 483–517.
Chantalat L., Jones N. D., Korber F., Navaza J., and Pavlovsky A. G. (1995) The crystal structure of wildtype growth hormone at 2.5 angstrom resolution. Prol. Pep. Lett. 2, 333–340.
Clackson T., Ultsch M. H., Wells J. A., and de Vos A. M. (1998) Structural and functional analysis of the 1:1 growth hormone, receptor complex reveals the molecularbasis for receptor affinity. J. Mol. Biol. 277, 1111–1128.
Clackson T. and Wells J. A. (1995) A hot spot of binding energy in a hormone-receptor interface. Science 267, 383–386.
Cokol M., Nair R., and Rost B. (2000) Finding nuclear localization signals. EMBO Rep. 1, 411–415.
Cunningham B. C., Ultsch M., de Vos A. M., Mulkerrin M. G., Clauser K. R., and Wells J. A. (1991) Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science 254, 821–825.
DeLano W. L. (2002) The PyMOL Molecular Graphics System. DeLano Scientific, San Carlos, CA.
De Palo E. F., De Filippis V., Gatti R., and Spinella P. (2006) Growth hormone isotorms and segments/fragments, molecular structure and laboratory measurement. Clin. Chim. Acta 364, 67–76.
De Palo E. F., Gatti R., Antonelli G., and Spinella P. (2006) Growth hormone isoforms, segments/fragments. Does a link exist with multifunctionality? Clin. Chim. Acta 364, 77–81.
de Vos A. M., Ultsch M., and Kossiakoff A. A. (1992) Human growth hormone and extracellular domain of its receptor, crystal structure of the complex. Science 255, 306–312.
Fraser R. A. and Harvey S. (1992) Ubiquitous distribution of growth hormone receptors and/or binding proteins in adenohypophyseal tissue. Endocrinology 130, 3593–3600.
Granot I., Halevy O., Tchelet A., et al. (1993) Effect of N-terminal modified analogs of growth hormone on collagen synthesis in avian skin fibroblasts. Mol. Cell. Endocrinol. 92, 241–246.
Guex N. and Peitsch M. C. (1997) SWISS-MODEL and the Swiss-Pdb Viewer, an environment for comparative protein modeling. Electrophoresis 18, 2714–2723.
Harvey S., Baudet M-L., and Sanders E. J. (2006) Evidence for the expression and translation of a novel growth hormone transcript in central and peripheral tissues of chick embryos. Neuropeptides 40, 151.
Harvey S. and Hull K. L. (2003) Neural growth hormone, an update. J. Mol. Neurosci. 20, 1–14.
Harvey S., Johnson C. D., and Sanders E. J. (2001) Growth hormone in neural tissues of the chick embryo. J. Endocrinol. 169, 487–498.
Harvey S., Johnson C. D., and Sanders E. J. (2000) Extrapituitary growth hormone in peripheral tissues of early chick embryos. J. Endocrinol. 166, 489–502.
Kossiakoff A. A. and de Vos A. M. (1999) Structural basis for cytokine-receptor recognition and receptor activation. Adv. Prot. Chem. 52, 67–108.
Krishnam K. A., Proudman J. A., and Bahr J. M. (1989) Avian growth hormone receptor assay, use of chicken and turkey liver membranes. Mol. Cell. Endocrinol. 66, 125–134.
Langenheim J. F., Tan D., Walker A. M., and Chen W. Y. (2006) Two wrongs can make a right, dimers of prolactin and growth hormone receptor antagonists behave as agonists. Mol. Endocrinol. 20, 661–674.
Lincoln D. T., Sinowatz F., Temmim-Baker L., Baker H. I., Kolle S., and Waters M. J. (1998) Growth hormone receptor expression in the nucleus and cytoplasm of normal and neoplastic cells. Histochem. Cell Biol. 109, 141–159.
Lobie P.E., Barnard R., and Waters M.J. (1991) The nuclear growth hormone receptor binding protein. Antigenic and physicochemical characterization. J. Biol. Chem. 266, 22,645–22,652.
Lobie P. E., Mertani H., Morel G., Morales-Bustos O., Norstedt G., and Waters M.J. (1994) Receptor-mediated nuclear translocation of growth hormone. J. Biol. Chem. 269, 21,330–21,339.
Lobie P. E., Wood T. J., Chen C. M., Waters M. J., and Norstedt G. (1994) Nuclear translocation and anchorage of the growth hormone receptor. J. Biol. Chem. 269, 31,735–31,746.
Macara I. G. (2001) Transport into and out of the nucleus. Microbiol. Mol. Biol. Rev. 65, 570–594.
Mertani H. C., Raccurt M., Abbate A., et al. (2003) Nuclear translocation and retention of growth hormone. Endocrinology 144, 3182–3195.
Monsonego E., Baunbach W. R., Lavelin I., Gertler A., Hurwitz S., and Pines M. (1997) Generation of growth hormone binding protein by avian growth plate chondrocytes is dependent on cell differentiation. Mol. Cell. Endocrinol. 135, 1–10.
Nakai K. and Horton P. (1999) PSORT, a program for detecting the sorting signals of proteins and predicting their subcellular localization. Trends Biochem. Sci. 24, 34–35.
Peitsch M. C. (1995) Protein modeling by e-mail. Bio/Technology 13, 658–660.
Rezvani I., Maddaiah V. T., Collipp P. J., Thomas J., and Chen S. Y. (1973) Kinetics of uptake and subcellular distribution of human growth hormone in liver slices. Biochem Med. 7, 432–440.
Sanders E. J., Walter M. A., Parker E., Aramburo C., and Harvey S. (2003) Opticin binds retinal growth hormone in the embryonic vitreous. Invest. Ophthalmol. Vis. Sci. 44, 5404–5409.
Schwede T., Kopp J., Guex N., and Peitsch M.C. (2003) SWISS-MODEL, an automated protein homologymodeling server. Nuc. Acids Res. 31, 3381–3385.
Silver P.A. (1991) How proteins enter the nucleus. Cell 64, 489–497.
Sundstrom M., Lundqvist T., Rodin J., Giebel L. B., Milligan D., and Norstedt G. (1996) Crystal structure of an antagonist mutant of human growth hormone, G120R, in complex with its receptor at 2.9 A resolution. J. Biol. Chem. 271, 32,197–32,203.
Takeuchi S., Haneda M., Teshigawara K., and Takahashi S. (2001) Identification of a novel GH isoform, a possible link between GH and melanocortin systems in the developing chicken eye. Endocrinology 142, 5158–5166.
Walsh S. T., Jevitts L. M., Sylvester J. E., and Kossiakoff A. A. (2003) Site2 binding energetics of the regulatory step of growth hormone-induced receptor homodimerization. Prot. Sci. 12, 1960–1970.
Waters M. J., Hoang H. N., Fairlie D. P., Pelekanos R. A., and Brown R. J. (2006) New insights into growth hormone action. J. Mol. Endocrinol. 36, 1–7.
Yoon J. B., Berry S. A., Seelig S., and Towle H. C. (1990) An induciblenuclear factor binds to a growth hormoneregulated gene. J. Biol. Chem. 265, 19,947–19,954.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Baudet, ML., Harvey, S. Small chicken growth hormone (scGH) variant in the neural retina. J Mol Neurosci 31, 261–271 (2007). https://doi.org/10.1385/JMN:31:03:261
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:31:03:261