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== HGH receptors and interactions == | == HGH receptors and interactions == | ||
<Structure load='1hgu' size='350' frame='true' align='right' caption='Representation of Somatotropin' /> | |||
The [https://en.wikipedia.org/wiki/Growth_hormone_receptor#:~:text=8%20External%20links-,Structure,GH%20binding%20protein%20(GHBP). GH membrane receptor (GHR)] is found on many cells and tissues with the exception of the brain, testicles and thymus. It is part of the [[https://en.wikipedia.org/wiki/Type_I_cytokine_receptor class I cytokine receptor family] [https://doi.org/10.1016/j.ygcen.2017.07.028 ]. The nature of this receptor is not fully understood, but it seems that it may be present in different forms due to different post-translational changes that may occur in a single protein.<ref name="m/s"> Le Cam, A. (1993), Mode d’action de l’hormone de croissance. médecine/sciences, 12:1352-61.[http://www.ipubli.inserm.fr/bitstream/handle/10608/2863/MS_1993_12_1352.pdf?sequence=1]</ref> | The [https://en.wikipedia.org/wiki/Growth_hormone_receptor#:~:text=8%20External%20links-,Structure,GH%20binding%20protein%20(GHBP). GH membrane receptor (GHR)] is found on many cells and tissues with the exception of the brain, testicles and thymus. It is part of the [[https://en.wikipedia.org/wiki/Type_I_cytokine_receptor class I cytokine receptor family] [https://doi.org/10.1016/j.ygcen.2017.07.028 ]. The nature of this receptor is not fully understood, but it seems that it may be present in different forms due to different post-translational changes that may occur in a single protein.<ref name="m/s"> Le Cam, A. (1993), Mode d’action de l’hormone de croissance. médecine/sciences, 12:1352-61.[http://www.ipubli.inserm.fr/bitstream/handle/10608/2863/MS_1993_12_1352.pdf?sequence=1]</ref> | ||
The hGH receptor is a [https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane protein] consisting of 620 amino acids. It has two extracellular domains which are highly conserved, each containing 7 β-sheets. The protein should theoretically have a molecular mass of 70 kDa considering the amino acid sequence. In fact the actual molecular weight is 100 - 130 kDa. This can be explained due to [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modifications] such as glycosylation and ubiquitination. Ligand binding increases ubiquitination and possibly has effect on GH receptor internalisation [https://doi.org/10.1016/B0-12-341103-3/00132-7]. | The hGH receptor is a [https://en.wikipedia.org/wiki/Transmembrane_protein transmembrane protein] consisting of 620 amino acids. It has two extracellular domains which are highly conserved, each containing 7 β-sheets. The protein should theoretically have a molecular mass of 70 kDa considering the amino acid sequence. In fact the actual molecular weight is 100 - 130 kDa. This can be explained due to [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modifications] such as glycosylation and ubiquitination. Ligand binding increases ubiquitination and possibly has effect on GH receptor internalisation [https://doi.org/10.1016/B0-12-341103-3/00132-7]. | ||
Binding to the receptor is the first step in the biological action of the hormone.<ref name="m/s"/> For the binding of a single hGH, two hGH receptors are needed. The hGH binds with its high affinity binding site 1 onto the extracellular domain of the first receptor and with the low affinity binding site 2 onto the extracellular domain of the second receptor <ref name="pubMed">PMID:17584122</ref> <ref name="Endokrynologika Polska">DOI:10.5603/EP.2013.0009</ref>. This leads to receptor [https://en.wikipedia.org/wiki/Protein_dimer homodimerization] and transmits the signal into the target cell [https://doi.org/10.1016/B978-012088484-1/50006-9]. Additionally, it induces a conformational change in the intrecellular domain of the GHR [https://doi.org/10.1016/j.ghir.2013.02.002]. The two binding sites are allosterically coupled, this effect focused among some residues centered around the interaction between Asp116 (hGH) and Trp169 (hGH-receptor2). <ref name="pubMed">PMID:17584122</ref> | Binding to the receptor is the first step in the biological action of the hormone.<ref name="m/s"/> For the binding of a single hGH, two hGH receptors are needed. The hGH binds with its high affinity binding site 1 onto the extracellular domain of the first receptor and with the low affinity binding site 2 onto the extracellular domain of the second receptor <ref name="pubMed">PMID:17584122</ref> <ref name="Endokrynologika Polska">DOI:10.5603/EP.2013.0009</ref>. This leads to receptor [https://en.wikipedia.org/wiki/Protein_dimer homodimerization] and transmits the signal into the target cell [https://doi.org/10.1016/B978-012088484-1/50006-9]. Additionally, it induces a conformational change in the intrecellular domain of the GHR [https://doi.org/10.1016/j.ghir.2013.02.002]. The <scene name='86/868194/Binding_sites/1'>two binding</scene> sites are allosterically coupled, this effect focused among some residues centered around the interaction between Asp116 (hGH) and Trp169 (hGH-receptor2). <ref name="pubMed">PMID:17584122</ref> | ||
The first binding site of the HGH protein contains parts of helices 1 and 4 (amino acids 103-119), as well as parts of the binding loop between helices 1 and 2 (amino acids 41-68). The second binding site contains the N-terminus and part of the third helix (amino acids 54-74). Major roles hereby play Phenylalanine 1 and Isoleucine 4 (N-terminus) and Aspartic acid 116 <ref name"pubMed">PMID: 1948064</ref>. The C-terminal part of the receptor, consisting of the last 165 amino acids, has no effect on GH binding.<ref name="m/s"/> <ref name="pubMed">PMID:17584122</ref> | The first binding site of the HGH protein contains parts of helices 1 and 4 (amino acids 103-119), as well as parts of the binding loop between helices 1 and 2 (amino acids 41-68). The second binding site contains the <scene name='86/868194/N_and_c_part/1'>N-terminus</scene> and part of the third helix (amino acids 54-74). Major roles hereby play Phenylalanine 1 and Isoleucine 4 (N-terminus) and Aspartic acid 116 <ref name"pubMed">PMID: 1948064</ref>. The C-terminal part of the receptor, consisting of the last 165 amino acids, has no effect on GH binding.<ref name="m/s"/> <ref name="pubMed">PMID:17584122</ref> | ||
Several GH variants with modified N-terminus were explored to learn more about the behaviour of the binding of the receptor molecule. A GH with an extension of Methionin on the N-terminus behave identical to an authentic GH in assays. The small, neutral amino acid without any side chains has no apparent effect on the binding of the receptor. In contrast, a removal of 13 amino acids at the N-terminus results in reduced binding activity to somatogenic receptors and decreased biological activity, because the amino acids 1 to 16 are involved in the binding site 2. But the other part of the binding site (with Trp103, Asp116 and Glu119 from helix 3) of the hGH molecule are intact and available for binding of the receptor. The N-terminus is required for full biological activity, however, additions still deletions can not completly abolish the functions of the molecule. <ref name="pubMed">PMID:17584122</ref> | Several GH variants with modified N-terminus were explored to learn more about the behaviour of the binding of the receptor molecule. A GH with an extension of Methionin on the N-terminus behave identical to an authentic GH in assays. The small, neutral amino acid without any side chains has no apparent effect on the binding of the receptor. In contrast, a removal of 13 amino acids at the N-terminus results in reduced binding activity to somatogenic receptors and decreased biological activity, because the amino acids 1 to 16 are involved in the binding site 2. But the other part of the binding site (with Trp103, Asp116 and Glu119 from helix 3) of the hGH molecule are intact and available for binding of the receptor. The N-terminus is required for full biological activity, however, additions still deletions can not completly abolish the functions of the molecule. <ref name="pubMed">PMID:17584122</ref> | ||
