Follicle-Stimulating Hormone Beta-Subunit (FSHB)

The protein hormone this research paper discusses is the follicle-stimulating hormone beta-subunit. This protein hormone in the case of this research paper belongs to humans, also known by their scientific name, Homo Sapiens.​ (Follicle-stimulating Hormone, 2019)

Production

FSHB is a protein hormone that is produced by the pituitary gland in the endocrine gland. More specifically, it is produced by the anterior pituitary gland. The anterior pituitary gland is composed of many hormonal cells. They differ from cells that contain polypeptide hormones and glycoprotein hormones. FSH is produced in the gonadotropic cells of the anterior pituitary glands. Gonadotropic cells produce the FSHB hormone to assist in reproduction. (Blanco & Blanco, 2017)

The gonadotropic cells of the anterior pituitary gland express FSHB when the hypothalamus secretes a hormone called Gonadotropin-releasing hormone (GnRH). GnRH stimulates the release of FSHB when ovulation occurs, which is around day 14, halfway through the ovarian cycle. Ovulation also coordinates with the menstrual cycle. These cycles occur monthly to prepare the uterus to implant the egg if fertilization occurs. The protein is expressed at the beginning of the ovarian cycle, where GnRH is stimulated by the hypothalamus. The hypothalamus is the region of the brain and the nervous system that stimulates the pituitary glands by releasing hormones. The GnRH then stimulates the release of FSH from the gonadotropic endocrine cells in the anterior pituitary glands into the bloodstream. The hormone then stimulates 60 to 20 oocytes that develop and surround themselves by follicle cells.

When the follicle is mature, the egg is released from the ovum and goes to the meiosis stage. In the male reproductive system, however, FSHB plays a similar yet different role. The male reproductive system does not have a uterus to produce the ovum from. FSHB is used to stimulate the Sertoli cells to secrete proteins necessary for spermatogenesis. Sertoli cells are supportive cells that completely surround the developing sperm in the seminiferous tubules, where the sperm is stored and produced. They supply nutrients to the spermatocytes and make sure sperm is sealed off from the bloodstream. The FSHB protein hormone does give negative feedback once secreted.

The release of FSHB also secretes estrogen. Estrogen, in the female reproductive system, is a steroid hormone that has a negative feedback on the anterior pituitary gland and inhibits the release of FSHB. However, as estrogen levels rise, it creates positive feedback on the hypothalamus to secrete GnRH, expressing FSHB once again. In the male reproductive system, testosterone has a negative feedback on the anterior pituitary gland to stop the secretion of FSHB. However, as levels of testosterone fall, the hypothalamus responds by secreting GnRH, which expresses FSHB, once again by the anterior pituitary gland. (DiGiuseppe, M., & Fraser, 2012)

The gene that codes for the protein FSHB is located on chromosome 11. More specifically on the short arm of the chromosome, on region 1, band 4 and sub-band 1. The location is also written as 11p14.1.

The length of the gene that codes for the FSHB protein are 30​ ,231,014 to 30,235,277 base pairs long. Introns are regions non-coding sequences on the DNA and RNA strand, which later alter the reading of the amino acid coding for the protein if not removed. In the gene coding for the FSHB protein, there are at least 3 introns. Exons are regions of sequences that do code for DNA and RNA in the gene. There are 3 exons in the gene coding for the FSHB protein. (Follicle-stimulating Hormone, 2019)​

Structure

The FSHB protein is 129 amino acids long. There are 2 molecular compounds in the structure for FSHB. The structure consists of an alpha subunit and a beta subunit. Owning an alpha and beta subunit gives this protein the identity of a heterodimer. The two polypeptides are similar in structure. They both happen to have similar folds, a cystine-knot motif center. These properties give the FSHB a crystal structure, indicating the two subunits make the polypeptide look symmetrical.

The cysteine-knot motif states there are 3 disulfide bridges in the center of each subunit (Mckusick, 2019). ​ Disulfide​ bridges in one of the bonds that are formed when an -SH group of two cysteine amino acids line up and react to form an S-S covalent bond. Due to it having cysteine amino acid residues, it is known to be a very strong bond and acts in stabilizing the protein, during the tertiary structure. The disulfide bridges confer the highly folded three-dimensional shape. The two subunits also differ in structure. The alpha-subunit consists of a single gene. The beta subunit consists of multiple genes. Each gene confers to each hormone specifically, resulting in the beta subunit to be hormone-specific. The beta-polypeptide in the sense is restrictively expressed and exhibits a more specific hormonal regulation. Below is a diagram of a 3D structure of the follicle-stimulating hormone beta polypeptide.

Diagram: Diaz, Van Roey, & Fox. (2001). 1FL7: HUMAN FOLLICLE STIMULATING HORMONE.​ Retrieved from https://www.ncbi.nlm.nih.gov/Structure/pdb/1FL7.

In the diagram, the pink portion refers to the alpha subunit of the polypeptide and the blue portion refers to the beta subunit. The molecules around the subunits are chemicals involved in interaction that occurs during the tertiary structure, causing the folding of the polypeptide. For instance, one of the chemicals in the structure is a sulfate ion, which is involved in disulfide bridges between the two subunits.

The secondary structure present in the structure of the polypeptide is the alpha-helix sheets and the beta-pleated sheets. The beta-pleated sheets are long, arrows in the middle. The alpha-helices are the thin, narrow and curly string-like structure all throughout the polypeptide. The alpha helices and beta-pleated sheet are formed from hydrogen bonding between the polypeptide. Which shows another secondary and tertiary structure interaction includes hydrogen bonding. Hydrogen bonding can occur between certain R-groups.

In the case of FSHB, hydrogen bonding occurs between certain carbohydrates and the amino acid tyrosine, known as tyr58. This interaction also helps to stabilize the 3D structure of the protein and give it the shape of alpha helices and beta-pleated sheets. In relevant information, the heterodimer structure helps the binding specificity of the FSHB protein. The receptor that FSHB binds to, FSHR (Follicle-stimulating hormone receptor) has G nucleotide-binding proteins. When FSHB binds to FSHR, The FSHB alpha and beta subunits dissociate. The alpha subunit carries on the water-soluble pathway for the protein. This pathway requires the protein to enter through the membrane using protein carriers and receptors such as FSHR, as it would be any other protein hormones, due to FSHB being polar and hydrophilic and the plasma membrane is highly non-polar and hydrophobic.

When binding to the G protein-coupled receptors on FSHR, the alpha-subunit activates adenylyl cyclase. Adenylyl Cyclase, once activated, catalyzes the reaction of ATP into Cyclic Adeno Monophosphate (cAMP). As cAMP levels increase, negative feedback on the FSHB increases and the steroid proteins such as estrogen in females and testosterone in males. (Cahoreau, Klett &​ Combarnous, 2015)

Function

Follicle-Stimulating Hormone Beta-Subunit protein functions in reproductive cells such as the gonads (ovaries and testes). The function of the protein is to stimulate the development of sex organs and gamete production in males and females. This is essential for meiosis to occur. Once ovulation is reached and an egg and sperm are available, division results in four gametes. The protein has different functions in both the male and female reproductive systems of homo sapiens, considering the differences in their reproductive systems.

In the female reproductive system, FSHB targets the ovary follicles to function in the development and maturation of ovarian follicles, as well as oocytes. There are steps to how the FSHB targets the ovary to help the maturation of ovarian follicles and oocytes. First, the menstrual cycle needs to begin. The menstrual cycle ensures that an ovum is released at the same time as the uterus is most receptive to a fertilized egg.

Diagram: Fung, J. (2018, November 8). PCOS and Hyperinsulinemia. Retrieved from​ https://medium.com/@drjasonfung/pcos-and-hyperinsulinemia-1350708ecc73.

A follicle is a cellular structure inside the ovary. Each follicle contains a single, immature ovum. In a single ovarian cycle, follicle matures and releases an ovum, causing ovulation. When FSHB is in effect, it stimulates the follicle containing the ovum to mature and help the ovum release. This is called the follicular stage of the cycle. As mentioned above, another function of FSHB is to stimulate the development of sexual organs. A newborn girl is born with a complete set of reproductive organs, but they are immature. FSHB initiates the maturation of those sexual organs when the hypothalamus initiates the release of GnRH from the nervous system, which initiates the release of FSH along with LH for the first time. The secretion of estrogen in the form of "estradiol" causes the maturation of that sexual organ. These include the development of the breasts, growth of body hair, widening of the pelvis and preparing as well as maintaining the uterus for implantation of the fertilized egg. (Nelson Bio Text).

In the male reproductive system, FSH functions to cause the maturation of their sexual organs. Although male boys when born posses the genitalia, the reproductive system does not function until males reach puberty. Around the ages of puberty, which ranges around age 12 to 16, the hypothalamus releases GnRH which expresses the FSH protein from the anterior pituitary gland. The negative feedback from the release of this protein secretes testosterone. The release of testosterone causes the testes to release sperm. This is due to FSH causing the Sertoli cells to produce sperm through the seminiferous tubules, which are long tubes that sperm proceeds. The production of sperm, in turn, provides the physical and biochemical support for proper development and maturation of germ cells. (Carter-Edwards & Abdulnour, 2011)​

Significance

The structure of FSHB can always be linked back to its function. The main function of FSHB is to target the gonad cells to help the development of sexual organs or production of ovaries and sperm. One way this is successful is through receptor binding to FSHR. FSHR is present on the plasma membrane of Sertoli cells in the testis and granulosa cells in ovaries. The FSHB binds to FSHR to activate the adenylyl cycline enzymes, increasing levels of cAMP to increase the production of steroid hormones that initiate negative feedback and help with menstruation, ovulation and sperm production.

One way this is achieved is through the heterodimer structure of the protein. The protein is a glycoprotein consisting of an alpha subunit and a beta subunit. These two subunits have different purposes in binding to the right receptor. The alpha-subunit binds to the high-affinity area of FSHR, which causes the change to the receptor activating adenylyl cycline and the beta-subunit makes sure it binds to the correct receptor. Recall, the beta-subunit of the protein is hormone specific, whereas the alpha-subunit can bind to any receptor. If the beta-subunit was not hormone specific, it would bind to other receptors used for other glycoproteins.

Such receptors include the receptors for LH, TSH, etcetera. These receptors lie on different target cells, and FSHB will not be able to target the gonad cells and complete its function of maintaining the reproductive cells. This is only possible if the structure is a heterodimer, if the protein has an alpha and a beta subunit.

Another structure that aids in the function of FSHB is the disulfide bridges. As mentioned above, the two subunits are connected by disulfide bridges. These disulfide bridges that occur during the tertiary structure determine the 3D structure of the polypeptide. These help with the function of the protein because the GnRH stimulates the release of FSHB from the​ cells in the anterior pituitary glands into the bloodstream. Once the protein enters the bloodstream, there are high chances the protein starts to lose its shape, due to the hydrophilic environment of both the bloodstream and the polypeptide being hydrophilic, causing the polypeptide to dissolve into the bloodstream. If the polypeptide loses its 3D shape, it denatures, it does not target the granulosa cells and Sertoli cells and is unable to function in developing and maintaining the reproductive cells. However, disulfide bridges are composed of cysteine amino acid residue and sulfur atoms, which has such a high covalent bond that it continues to stabilize the protein and make sure the structure of the protein does not get denatured (​ Cahoreau, Klett & Combarnous, 2015).

It is important to realize the​ FSHB protein is a protein essential to life. Without FSHB, the body would need to find another way to develop the sexual organs. Without FSHB, the body would have to find another way to process spermatogenesis and oogenesis. Both these processes for germ cells are not possible if the release of FSHB does not initiate ovulation or the production of sperm. For instance, it is very possible to have a deficiency of the FSHB protein from the pituitary gland.

There are many cases where the deficiency of the protein resulted in hypogonadism. Hypogonadism is the failure of reproductive organs due to low production of hormones. Improper function of FSHB can also result in hypogonadism. For instance, in the case of a 27-year-old woman, who was found positive for hypogonadism, the gene coding for the FSHB protein had a 2 base-pair deletion. Due to the deletion of base-pairs on the mRNA strand, the reading frame coding for the FSH protein was altered. The synthesis of FSH protein was a failure, resulting in low sex hormones to be produced. Hypogonadism affected the woman by causing infertility for 6 years. After 6 years she was able to conceive her first child. Other symptoms affecting the woman due to such low expression of the FSH protein include loss of body hair, decreased muscle mass (hypogonadal bone loss) and depression.

There are other cases where the expression of the protein is too high in the body. Such high expression may result in menopause as a symptom. FSH levels are known to be the highest right before ovulation. The gland will keep on stimulating FSH in the body until ovulation occurs. If FSH levels remain expressed and elevated for a certain period of time, this indicates ovulation has not occurred. Ovulation is not striking, leading to diminished menstruation, developing menopause. In menopause, the capability of the female reproductive system comes to an end and menstruation ceases to stop. (Mckusick, 2019)

Bibliography

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FSHB follicle stimulating hormone subunit beta [Homo sapiens (human)] - Gene - NCBI. (n.d.). Retrieved from https://www.ncbi.nlm.nih.gov/gene/2488#general-gene-info.

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