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From Proteopedia
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Somatotropin and Genetic origin
Somatotropin (GH for Growth Hormone or HGH for Human Growth Hormone) is a polypeptide hormone produced by the somatotropic cells of the pituitary gland. The Human Growth Hormone, a protein circulating in the blood, has its origin on chromosome 17. There it gets encoded by the Growth hormone 1 gene along with four other related genes. Three of these genes are encoding human chorionic somatomammotropin, which is closely related to somatotropin. They are all in the same transcriptional orientation.
Functions
Somatropin plays an important role in physiological environments such as: increasing muscle mass, reducing fat mass, providing the energy necessary for tissue growth, maintaining the right level of glucose and lipids... and the development of the individual's body [1]. It acts directly on a cell surface or indirectly. In the second case, somatotropin stimulates tissues such as the liver, which in turn allows the synthesis and secretion of IGF-1, thus enabling the development of cell growth, tissue, bone and thus the linear growth of the individual.[2]
Structure
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Somatotropin has two major isoforms. The predominant form is composed out of 191 amino acids and has a molecular weight of 22 kDa. The second isoform lost amino acids 32 till 46 due to alternative splicing of the pre-mRNA and therefore has a molecular weight of 20 kDa.
The primary structure, corresponding to a sequence of amino acids, of the predominant somatotropin is the following : PUT IMAGE
Somatotropin does not exist as a linear chain of amino acids, it twists and folds on itself, forming the secondary structure. The protein consists of four antiparallel aligned α-helices. The first helix starts at the 6th amino acid, which is a leucine and ends with the 37th amino acid proline. It is separated from the other three helices after the 37th position. The 38th and 39th amino acids, which are lysine and glutamic acid are spliced out of the protein and therefore disconnects the first helix from the second one. The second helix starts at position 72 till 92, the third from 106 till 128 and the fourth helix from 155 until 184. From the secondary structure, we obtain the tertiary structure, which corresponds to the 3D structure adopted by all the alpha helixes. The structural maintenance is ensured by electrostatic, hydrophobic, hydrogen and/or covalent interactions with cysteine 53 and cysteine 165 that form a disulphide bridge as well as cysteine 182 with cysteine 189. The protein has two different binding sites: both located at the ends of the protein, the N-terminus as well as the C-terminus.3
HGH receptors and interactions
The gene coding for the GH receptor is located on chromosome 5, it contains 9 exon and 87 kb. The complementary DNA, synthesised from an mRNA, representing the coding part of the genome, has been transcribed during reverse transcription and therefore contains only the exons. This DNA codes for a 626 amino acid protein containing the signal peptide, an extracellular domain highly conserved, an hydrophobic transmembrane domain, and a variable intracellular domain. The GH membrane receptor is found on many cells and tissues with the exception of the brain, testicles and thymus.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.[3]
The HGH receptor is a transmembrane protein consisting of 620 amino acids. It has two extracellular domains, 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 post-translational modifications such as glycosylation and ubiquitination. Ligand binding increases ubiquitination and possibly has effect on GH receptor internalisation.
Binding to the receptor is the first step in the biological action of the hormone.[3] For the binding of a single HGH, two HGH receptors are needed. The HGH binds with one of its binding sites onto the extracellular domain of the first receptor and with the other binding site onto the extracellular domain of the second receptor. This leads to receptor homodimerization and transmits the signal into the target cell. The first binding site of the HGH protein contains parts of helices 1 and 4, as well as part of the binding loop between helices 1 and 2. The second binding site contains the N-terminus and part of the third helix. Major roles hereby play Phenylalanine 1 and Isoleucine 4 (N-terminus) and Aspartic acid 116. The C-terminal part of the receptor, consisting of the last 165 amino acids, has no effect on GH binding.[3]
The hormone-binding extracellular domain consists of 250 amino acids, including several cysteine residues which are conserved and can form disulphide bridges.The intracellular domain of the receptor is made up of 350 amino acids, it represents the least conserved region and is made up of 10 tyrosine residues likely to be phosphorylated by tyrosine kinase (JAK2), during the formation of the GH-receptor complex. A reaction cascade involving kinase enzymes is then activated, allowing the expression of certain genes coding for proteins or not, necessary for biological activity. It therefore controls the expression of certain genes such as the gene coding for the IGF-1 factor. The liver and adipose tissue being important targets for GH, it therefore contributes to metabolic homeostasis.[3]
Dieseas and treatments
Many diseases can be due to a dysfunction in the secretion of GH. Dwarfism is characterized by a lack of GH. The reasons for this deficiency can be explained by many fact, as welle as : a dysfunction during foetal development,The inability of somatotropic cells to synthesize GH, an abnormal structure of the protein, making the connection to the receiver more difficult, geneics mutation ... These factors are then likely to lead to a slowdown in growth, cell, tissue, and bone development.[4] Gigantism is characterised by the presence of a high level of GH or IGF-1. This pathology is most often due to an adenoma of the pituitary cells, responsible for the production of the hormone GHRH, which then stimulates the cells to produce GH in large quantities. It can also be explained by the fact that tissues that do not normally produce GH have tumour cells capable of producing GH. Acromegaly is when this excess of hormone occurs after puberty.[4]
Until 1985, injections of GH were carried out for people suffering from dwarfism. As it could only be obtained by extraction from the pituitary glands of dead people, it could only be extracted in small quantities, so resources were limited.[5] Also this therapeutic treatment has been stopped in many countries, due to the possible contamination of the hormone by prions, which can cause serious diseases such as Creutzfeldt-Jakob disease.[4] As a result, biosynthetic synthesis of the hormone is carried out by developing recombinant proteins of GH or IGF-1.[5]
Affected by gigantism pathology, individuals may have therapeutic radiation and therapeutic drug treatment or synthesis of inhibitors such as somatostatin,[4] which act as GH antagonists by binding to the receptor, thus preventing the GH to perform its functions.
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References
- ↑ Reh CS, Geffner ME. Somatotropin in the treatment of growth hormone deficiency and Turner syndrome in pediatric patients: a review. Clin Pharmacol. 2010;2:111-22. doi: 10.2147/CPAA.S6525. Epub 2010 Jun 1. PMID:22291494 doi:http://dx.doi.org/10.2147/CPAA.S6525
- ↑ Utiger, R. D. and other Encyclopedia Britannica Contributors (1998), Insulin-like growth factor. Science, Chemistry.
- ↑ 3.0 3.1 3.2 3.3 Le Cam, A. (1993), Mode d’action de l’hormone de croissance. médecine/sciences, 12:1352-61.[1]
- ↑ 4.0 4.1 4.2 4.3 Utiger, R.D. and other Encyclopedia Britannica Contributors (1998), Growth hormone. Life cycle, processes & properties encyclopedia articles.
- ↑ 5.0 5.1 Dr. Abdi, M., Département de Génétique Moléculaire et Appliquée, Université des Sciences et de la Technologie d’Oran Mohamed BOUDIAF.
