Human growth hormone: Difference between revisions
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HGH is phosphorylated on Ser residues 132 and 176 (Giorgianni, Beranova-Giorgianni, and Desiderio, 2004)<ref>PMID:14997482</ref>. Other research has indicated possible phosphorylation of Tyr residues 35 and 42. However, these phosphorylations were only investigated in carcinoma cells with constitutively active epidermal growth factor-stimulated tyrosine kinase (Baldwin et al., 1983)<ref>PMID:6600511</ref>. The overall influence of these post-translational modifications on hGH activity has yet to be determined. | HGH is phosphorylated on Ser residues 132 and 176 (Giorgianni, Beranova-Giorgianni, and Desiderio, 2004)<ref>PMID:14997482</ref>. Other research has indicated possible phosphorylation of Tyr residues 35 and 42. However, these phosphorylations were only investigated in carcinoma cells with constitutively active epidermal growth factor-stimulated tyrosine kinase (Baldwin et al., 1983)<ref>PMID:6600511</ref>. The overall influence of these post-translational modifications on hGH activity has yet to be determined. | ||
<StructureSection load='1hgu' size='350' side='right' caption='Human growth hormone (PDB entry [[1hgu]])' scene=''> | |||
==Function== | |||
'''Human growth hormone''' (hGH) plays a vital role in growth and development. It is naturally produced by somatotropic cells in the anterior pituitary gland. The [[hormone]] is produced as a 217 amino acid precursor protein. The 26 N-terminal amino acids correspond to a signal peptide, which is essential for hormone secretion. This signal peptide is cleaved during the secretion process to yield the mature, 191 amino acid form of hGH. | |||
Mature hGH travels through the bloodstream and interacts with a specific hGH-receptor on the surface of various cells, including muscle, bone, and cartilage. Binding of hGH to its receptor causes dimerization and signal transduction, which ultimately stimulates cellular division. HGH also indirectly influences growth by stimulating the liver to produce additional growth factors, such as insulin-like growth factor-1. Synthetic versions of hGH produced by recombinant DNA technology are used to treat growth disorders associated with hGH deficiencies. [[Prolactin receptor]] (PRLR) can also bind to and be activated by growth hormone. | |||
==Location in the Body== | |||
hGH is produced in the anterior pituitary gland or hypophyse and is located at the base of the brain. The hormones then circulate throughout the vascular system of the body. The pituitary gland helps control growth as well as blood pressure, energy management, all functions of the sex organs, thyroid glands and metabolism, temperature regulation and pain relief. hGH interacts with a variety of cells while in the bloodstream including muscle and bone cells. It eventually reaches and stimulates growth of all major organs (particularly the liver where it stimulates the production of growth factors) with the exception of the brain. | |||
==Growth Hormone’s Signal Peptide== | |||
Human growth hormone exists in two forms, pre-GH and mature GH. The pre-protein contains a 26 residue-long signal peptide located on the N-terminus of the protein, which is cleaved off to create the mature protein. | |||
The signal peptide acts as an anchor to keep the pre-protein bound to the membrane of the endoplasmic reticulum (ER). Following proper signaling, an ER membrane-bound signal I peptidase cleaves the 217 amino acid long pre-protein between residues 26 and 27 resulting in the 191 residue-long mature secretory GH (Chawla 1983; Tuteja 2005)<ref>PMID:6344776</ref>. The now active protein releases from the membrane into the ER lumen and is exported out of the cell. | |||
Mutations to residues within the signal peptide have show to affect the secretion of GH from the cell. Specifically, the Lys16Pro variant is associated with decreased levels of GH due to suppressed secretion, resulting in growth hormone deficiency isolated type 1B (IGHD1B) (Millar D.S. 2003)<ref>PMID:12655557</ref>. | |||
==Isoforms== | |||
There are four natural splice variants, or isoforms, of human growth hormone that have been identified. The different isoforms are produced when splicing of the five exons occurs at various positions. Note that in all four isoforms, the first 26 amino acids on the N-terminus are only present in the precursor form, and are not part of the active hormone. The 22KD GH (22 K-GH) is the most prominently found variant and is deemed as the canonical sequence, meaning that it serves as the reference to the other isoforms in terms of location of features. Is is followed by 20KD GH(20 K-GH) and other rare isoforms. One of the key differences about the other isoforms is that since they are lacking certain sections of amino acids, then the single point mutations that naturally occur in those regions will not affect the function or activity of the isoform proteins. For example, there several single point mutations that occur in the range of amino acids 58 through 72 that result in reduced ability to activate the JAK/STAT pathway (Millar et al., 2003). This section is absent in isoform 2, and therefore that variant of the protein is not susceptible to such alterations. Similarly, there are single point mutations in the range of amino acids 111 through 148 and 117 through 162 that result in reduced secretion (Millar et al., 2003), reduced ability to activate the JAK/STAT pathway (Millar et al., 2003), and loss of activity (Takahashi et al., 1997)<ref>PMID:9276733</ref>. Therefore, since isoforms 2 and 3 are lacking these regions, they are not subject to these various effects on activity. | |||
Isoform 1 (GH1) (191 amino acids; MW = 24,847 kDa) | |||
The GH1 is expressed mainly in somatotrope cells of the pituitary gland. This 22 K-GH molecule is the main GH isoform, representing more than 90% of total GH in circulation. Its tertiary structure is a 4-helical twisted bundle with unusual connectivity. The helices run up-up-down-down instead of the more usual up-down-up-down form. | |||
GH is best known from its growth promoting activity in children, but also has import- ant biological activities in adults. These include lipolysis, glucose-, calcium- and phosphorous-metabolism as well as lactogenesis and immune function. | |||
MATGSRTSLL LAFGLLCLPW LQEGSAFPTI PLSRLFDNAM LRAHRLHQLA FDTYQEFEEAYIPKEQKYSF LQNPQTSLCF SESIPTPSNR EETQQKSNLE LLRISLLLIQ SWLEPVQFLR SVFANSLVYG ASDSNVYDLL KDLEEGIQTL MGRLEDGSPR TGQIFKQTYS KFDTNSHNDDALLKNYGLLY CFRKDMDKVE TFLRIVQCRS VEGSCGF | |||
Isoform 2 (176 amino acids; MW = 22,992 kDa; Missing amino acids 58-72) | |||
The second most abundant GH isoform is the 20 K-GH molecule. It is derived from GH-1 by alternative pre-messenger ribonucleic acid (pre mRNA) splicing of exon 3. The structure is similar to 22 K-GH except for a de- letion of the internal residues 32–46. Therefore, 20 K-GH consists of 176 amino acids only. | |||
There is compelling evidences that both 22 K- and 20 K-GH can activate Janus Kinase 2 (JAK2), signal transducers and activators of tran- scription 1, 3 and 5 (STATs 1/3/5), although the level of STAT 1/3/5 phosphorylation induced by 22 K-GH are higher than those of 20 K-GH [18]. | |||
MATGSRTSLL LAFGLLCLPW LQEGSAFPTI PLSRLFDNAM LRAHRLHQLA FDTYQEFNPQTSLCFSESIP TPSNREETQQ KSNLELLRIS LLLIQSWLEP VQFLRSVFAN SLVYGASDSNVYDLLKDLEE GIQTLMGRLE DGSPRTGQIF KQTYSKFDTN SHNDDALLKN YGLLYCFRKDMDKVETFLRI VQCRSVEGSC GF | |||
Isoform 3 (153 amino acids; MW = 20,561 kDa; Missing amino acids 111-148) | |||
MATGSRTSLL LAFGLLCLPW LQEGSAFPTI PLSRLFDNAM LRAHRLHQLA FDTYQEFEEAYIPKEQKYSF LQNPQTSLCF SESIPTPSNR EETQQKSNLE LLRISLLLIQ TLMGRLEDGSPRTGQIFKQT YSKFDTNSHN DDALLKNYGL LYCFRKDMDK VETFLRIVQC RSVEGSCGF | |||
Isoform 4 (145 amino acids; MW = 19,802 kDa; Missing amino acids 117-162) | |||
MATGSRTSLL LAFGLLCLPW LQEGSAFPTI PLSRLFDNAM LRAHRLHQLA FDTYQEFEEAYIPKEQKYSF LQNPQTSLCF SESIPTPSNR EETQQKSNLE LLRISLLLIQ SWLEPVQIFKQTYSKFDTNS HNDDALLKNY GLLYCFRKDM DKVETFLRIV QCRSVEGSCG F | |||
==Structure== | |||
'''Primary Sequence'''<br/> | |||
hGH is produced within the cell as a pre-protein, consisting of a 191 polypeptide chain associated with a 26 amino acid signal peptide. This signal peptide functions in membrane translocation, and is eventually cleaved to yield the mature form of hGH-1. The signal peptide is cleaved from the 191 polypeptide chain of hGH-1 by an ER membrane-bound protease (Chawla, Parks, and Rudman, 1983) | |||
MATGSRTSLLLAFGLLCLPWLQEGSAFPTIPLSRLFDNAMLRAHRLHQLAFDTYQEF | |||
EAYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQFR | |||
SVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSH | |||
NDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGSCGF | |||
Primary Sequence of hGH-1 precursor | |||
Primary Sequence Variations between Isoforms: | |||
hGH-1 (most abundant isoform): has a primary amino acid sequence of 191 amino acids | |||
Isoform 2: amino acid residues 58-72 of hGH-1 are excluded | |||
Isoform 3: excludes amino acid residues 111-148 | |||
Isoform 4: excludes amino acid residues 117-162 | |||
'''Secondary Structure'''<br/> | |||
hGH is a single chain peptide, which was 45% helical with 8 α-helices (Chantalat et al., 1995)<ref>PMID:11435116</ref>. Protein Data Bank (PDB) provides predicted secondary structures of different proteins using the research from the paper and an algorithm program. | |||
'''Tertiary Structure'''<br/> | |||
The known crystal structure of hGH illustrate that the core of the protein is a four-helix bundle. Helices 1 & 4 at the NH2 and COOH ends are longer than helices 2 & 3 (Abraham 1992). A short loop connects helices 2 & 3 and two long crossover connections link helices 1 & 2 and helices 3 & 4. The helices run up-up-down-down (Abraham 1992). This is unusually because normally four helix bundles exhibit up-down-up-down orientation. | |||
An additional three much smaller helices exist within the connecting loops: one at beginning of the connection between helices 1& 2, one at the end of the connection between helices 1 & 2, and one in the short loop connection between helices 2 & 3 (Abraham 1992). | |||
==Post-translational modifications== | |||
'''Glycolysation'''<br/> | |||
Glycosylation helps distinguish between different variants and isoforms as it works as an ID cards for proteins. These carbohydrates are specific to each forms and are recognized by the associated hgH receptors. Though still being a relatively unknown mechanism in hgH, tudies have shown that one isoform in particular, a 22kDa variant was identified and discovered mostly due to the specific carbohydrates linked to the polypeptide chain. | |||
==Receptor Binding Site== | ==Receptor Binding Site== | ||