Chorionic gonadotropin beta

Last updated
CGB3
PBB Protein CGB image.jpg
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases CGB3 , CGB5, CGB7, CGB8, hCGB, CGB, Chorionic gonadotropin beta, chorionic gonadotropin beta subunit 3, Choriogonadotropin subunit beta, chorionic gonadotropin subunit beta 3, LHB, β-hCG
External IDs HomoloGene: 37338 GeneCards: CGB3
Orthologs
SpeciesHumanMouse
Entrez

1082

n/a

Ensembl

ENSG00000104827

n/a

UniProt

P0DN86

n/a

RefSeq (mRNA)

NM_000737

n/a

RefSeq (protein)

n/a

Location (UCSC) Chr 19: 49.02 – 49.02 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Choriogonadotropin subunit beta (CG-beta) also known as chorionic gonadotrophin chain beta is a protein that in humans is encoded by the CGB gene. [3] [4] [5]

Contents

This gene is a member of the glycoprotein hormone beta chain family and encodes the beta 3 subunit of chorionic gonadotropin (CG). Glycoprotein hormones are heterodimers consisting of a common alpha subunit and a unique beta subunit which confers biological specificity. CG is produced by the trophoblastic cells of the placenta and stimulates the ovaries to synthesize the steroids that are essential for the maintenance of pregnancy. The beta subunit of CG is encoded by 6 genes which are arranged in tandem and inverted pairs on chromosome 19q13.3 and contiguous with the luteinizing hormone beta subunit gene. [3]

Structure

CGB is composed of 165 amino acids, and has a molecular weight of 17.739 kDa. On this polypeptide, there are 7 total sites of glycosylation, encompassing 28 total N-linked glycans at 2 sites and 15 total O-linked glycans at 5 sites. The sites of N-glycoslylation occur at Asn33 and Asn50. The sites of O-glycoslyation occur at Ser138, Ser141, Ser147, Ser152, and Ser158. There are also three sites of phosphorylation, occurring at Ser86, Ser116, and Thr117. There are six disulfide pairings, occurring at 9-57, 23-72, 26-110, 34-88, 38-90, and 93-100. [6] Additionally, there are 10 known locations of mutation on the CGB polypeptide, occurring at amino acid positions 33, 35, 50, 52, 137, 138, 141, 147, 152, and 158. There is an alpha helix from amino acid positions 1-15, and a turn from positions 115-117. There are also beta sheets from positions 47-60, 67-69, 75-88, 99-112, and 118-121. [7] [8] [9] The polypeptide of CGB is also unusually flexible when compared to other polypeptides of similar structure and function. Its level of glycosylation has also been referred to as an 'extreme concentration', with baseline Human Chorionic Gonadotropin (hCG) being 30% glycosylated by weight, up to the 42% glycosylation of the 'hyperglocysolated hCG' by weight. [10] It is important to note here that the whole hCG protein hormone is a heterodimer, with an alpha and a beta subunit. The alpha subunit is identical in the hCG protein hormone, the Luteinizing Hormone (LH), the Follicle Stimulating Hormone (FSH), and the Thyroid Stimulating Hormone (TSH). It is specifically the beta subunit for each of these hormones that determines its specificity and function. Even further, the beta subunits of hCG, LH, FSH, and TSH show a high degree of sequence similarity in the first 114 amino acids of the polypeptide, with LH showing 85% similarity, LH showing 36% similarity, and TSH showing 46% similarity. One likely reason for such high sequence similarity in hCG and LH is the fact that both respective beta subunits both bind to the same receptor, with their homology illustrating a common biological function and biochemical pathway. [6]

Amino acid sequence of CGB, with sites of glycosylation, mutation, and phosphorylation notated CGB3 Amino Acid Sequence.png
Amino acid sequence of CGB, with sites of glycosylation, mutation, and phosphorylation notated

Coding and Homology

The very first nucleotide sequence of the gene encoding for the beta subunit of human chorionic gonadotropin (CGB) suggests that CGB evolved from a duplicate copy of the beta subunit of LH, another glycoprotein hormone with significant influence over pregnancy, expressed in the anterior pituitary gland. Subsequent nuclear mapping has found that humans possess six copies of the CGB gene, amazingly found together with the LHB gene on chromosome 19q13.33. Human CGB and LHB genes share an extremely high degree of similarity in their sequences, clocking in at 94% similarity. [11] This nucleotide sequence is encompassed by 3 exons. [12] Of the six genes that encode for CGB, four of them are functional. These include CGB, CGB5, CGB7, and CGB8. These four genes share a 97-99% DNA sequence similarity, and code for the biochemically functional beta subunit of hCG. Although CGB1 and CGB2 genes are similar in sequence to the other four genes previously mentioned (85%), they encode for a novel hypothetical protein that is 132 amino acids in length and does not share any homology to the functional CGB subunit. This particular result was caused by a DNA fragment insertion into the 5' untranslated region (UTR) of the CGB1 and CGB2 genes, giving way to a novel exon one and creating a single basepair open reading frame shift for exons two and three. [13]

Function

While the whole hCG glycoprotein hormone is a heterodimer consisting of an alpha and a beta subunit, it is the beta subunit alone that is responsible for the specificity of function of hCG. Thus, in this section, we will be referring to hCG as the specific beta subunit CGB, due to the subunit being solely responsible for its relevant function in pregnancy. CGB is only produced by the human body during pregnancy. CGB is the very first specific molecule synthesized by the embryo, with its RNA transcribed as early as the eight-cell stage. It is the trophoblast, which is the outer layer of the blastocyst, that first synthesizes this glycoprotein hormone. The blastocyst will become the embryo, and the trophoblast will eventually become part of the placenta. The blastocyst/trophoblast release CGB into the uterine space, which is somehow able to reach the hCG/LH receptor on the endometrial surface. Again, it is specifically the beta subunit of hCG (and also LH) that binds to the receptor, as the alpha subunits of both hormones, as well as FSH and TSH, are the same. This nonvascular communication by CGB is highly remarkable, and it is still not fully understood how CGB is able to communicate with the endometrial surface without being attached to it. Binding of CGB to the hCG/LH receptor prepares the endometrium for the impending implantation of the blastocyst. CGB implements immunotolerance and angiogenesis at the endometrial maternal-fetal interface, which is particularly critical to the establishment of a successful pregnancy. [14] By stimulating this angio- and vasculogenesis, CGB provides the placenta with a sufficient maternal blood supply, thus providing the embryo with the crucial nutrition it needs during its invasion of the uterine endometrium. [15] [16] As a more comprehensive overview: CGB promotes progesterone production by corpus luteal cells, promotes angiogenesis in uterine vasculature, promotes the fusion of cytotrophoblast cells and the subsequent differentiation to make syncytiotrophoblast cells, promotes the blockage of any immune or macrophage action by the maternal immune system on foreign invading placental cells, initiates proper and appropriate uterine growth parallel to fetal growth, suppresses any myometrial contractions during the course of pregnancy, stimulates growth and differentiation of the umbilical cord, prepares the endometrium for the approaching embryo implantation, acts on a receptor in mother's brain causing severe nausea and vomiting, and has also been shown to promote the growth of fetal organs during pregnancy. [17]

Immunomodulatory Properties

One critical action of CGB, among many, is the immunomodulatory effects that it has on the maternal response to the embryo. This activation of a highly specific immune system tolerance to the embryo is essential to preventing the rejection of the embryo by the maternal immune system, and therefore the successful embryo development and implantation. While miscarriages and spontaneous abortions obviously have a multitude of different causes, the maternal immune response to the implanting embryo is one of the major ones, with specific action being related to CD4+ T cells of the immune system. In order to effectively describe their influence on whether a pregnancy is successful or not, a brief overview of these cells is needed. They are classified into 4 different subsets: T helper (Th) 1, Th2, Th17, and T regulatory (Treg) cells. Studies have indicated that patients who suffer from recurrent miscarriages possess an immunity dominated by what is called the Th1/Th2 hypothesis. But subsequent studies have shown that the Th1/Th2 paradigm is not sufficient to describe the immunological affects by which the fetus is rejected, and has thus been expanded to the Th1/Th2/Th17 and Treg cell paradigm. Th17 and Treg cells, according to the field of immunology, have been described as lymphocyte subsets that show a clear differentiation from Th1 and Th2 cells. They play a major role in the development of autoimmune diseases and infection. Multiple studies have reported that a Th17/Treg imbalance is associated with recurrent spontaneous abortion. And while many studies have discussed and illustrated the immunosuppressive effects of CGB on T-cell proliferation, others have shown a contradictory trophic effect, further deepening the notion of an immunosuppressive pregnancy environment brought on by CGB. CGB encourages trophoblast invasion and interstitial theca cell proliferation through the overmodulation of extracellular-regulated kinase (ERK) and AKT signals, and the instigation of leptin production by CGB requires a dialogue between cAMP and p38 signaling pathways in the syncytiotrophoblast. It has also been shown that CGB has a positive impact on the proliferation of CD4+25+ T cells and that it attracts these cells to the endometrium in early pregnancy. Immune cells located at the implantation site actively contribute to embryo implantation. And so, through the modulation of inflammatory-promoting Th1 cells and anti-inflammatory Th2 cells, CGB plays a critically important role in the successful implantation of the embryo to the endometrial wall. [15] [16]

Vasculogenic and Angiogenic Properties

The angiogenic effect of CGB on endothelial cells is precisely mediated through the activation of hCG/LH receptor and PKA/cAMP pathway. It is through the binding of CGB to the hCG/LH receptor that the PKA/cAMP pathway is activated, which then helps stimulate angiogenesis and the establishment of a two-way nutrient highway for the embryo and subsequent fetus. Dibutyryl cAMP then stimulates vessel outgrowth from aortic ring, which further suggests the importance of the PKA pathway, as well as its preceding CGB pathway, during this angiogenic response. And so, clear direct angiogenic effects of CGB have been observed and substantiated on endothelial cells in the aortic ring, CAM, matrigel plug, and endothelial cell proliferation. In a normal pregnancy, CGB expression is associated with endometrial stimulation of angiogenesis occurring early in gestation, while also increasing the blood supply and altering the uterine vasculature through vasodilatation, increasing permeability, development, and maturation of new vessels. [18] [16]

Stimulation of Other Relevant Pregnancy Hormones

CGB triggers the body to create more estrogen and progesterone. In tandem with CGB, the increased estrogen and progesterone signal to the body that pregnancy is occurring, and help thicken the uterine lining and stop menstruation. It is the precise balance of these three hormones that help to sustain and maintain a healthy pregnancy. [19] More specifically, CGB is a luteotropic hormone that promotes the survival and steroidogenic activity of corpus luteum by acting through luteinizing hormone receptors (LHRs) expressed on luteinized theca and granulosa cells. Through this activation, the corpus luteum produces the progesterone needed for the subsequent stages of pregnancy. This helps to keep the highly crucial corpus luteum alive and activated. [20] [17]

Related Research Articles

<span class="mw-page-title-main">Endometrium</span> Inner mucous membrane of the mammalian uterus

The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional layer thickens and then is shed during menstruation in humans and some other mammals, including apes, Old World monkeys, some species of bat, the elephant shrew and the Cairo spiny mouse. In most other mammals, the endometrium is reabsorbed in the estrous cycle. During pregnancy, the glands and blood vessels in the endometrium further increase in size and number. Vascular spaces fuse and become interconnected, forming the placenta, which supplies oxygen and nutrition to the embryo and fetus. The speculated presence of an endometrial microbiota has been argued against.

<span class="mw-page-title-main">Menstrual cycle</span> Natural changes in the human female reproductive system

The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that makes pregnancy possible. The ovarian cycle controls the production and release of eggs and the cyclic release of estrogen and progesterone. The uterine cycle governs the preparation and maintenance of the lining of the uterus (womb) to receive an embryo. These cycles are concurrent and coordinated, normally last between 21 and 35 days, with a median length of 28 days, and continue for about 30–45 years.

<span class="mw-page-title-main">Luteinizing hormone</span> Gonadotropin secreted by the adenohypophysis

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

<span class="mw-page-title-main">Human chorionic gonadotropin</span> Hormone

Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo, which eventually forms the placenta after implantation. The presence of hCG is detected in some pregnancy tests. Some cancerous tumors produce this hormone; therefore, elevated levels measured when the patient is not pregnant may lead to a cancer diagnosis and, if high enough, paraneoplastic syndromes, however, it is not known whether this production is a contributing cause, or an effect of carcinogenesis. The pituitary analog of hCG, known as luteinizing hormone (LH), is produced in the pituitary gland of males and females of all ages.

<span class="mw-page-title-main">Follicle-stimulating hormone</span> Gonadotropin that regulates the development of reproductive processes

Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.

<span class="mw-page-title-main">Blastocyst</span> Structure formed around day 5 of mammalian embryonic development

The blastocyst is a structure formed in the early embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the embryoblast which subsequently forms the embryo, and an outer layer of trophoblast cells called the trophectoderm. This layer surrounds the inner cell mass and a fluid-filled cavity known as the blastocoel. In the late blastocyst, the trophectoderm is known as the trophoblast. The trophoblast gives rise to the chorion and amnion, the two fetal membranes that surround the embryo. The placenta derives from the embryonic chorion and the underlying uterine tissue of the mother.

<span class="mw-page-title-main">Corpus luteum</span> Temporary endocrine structure in ovaries

The corpus luteum is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is the remains of the ovarian follicle that has released a mature ovum during a previous ovulation.

Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/chorionic gonadotropins, human chorionic gonadotropin (hCG) and equine chorionic gonadotropin (eCG), as well as at least two forms of fish gonadotropins. These hormones are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. LH and FSH are secreted by the anterior pituitary gland, while hCG and eCG are secreted by the placenta in pregnant humans and mares, respectively. The gonadotropins act on the gonads, controlling gamete and sex hormone production.

Luteolysis is the structural and functional degradation of the corpus luteum, which occurs at the end of the luteal phase of both the estrous and menstrual cycles in the absence of pregnancy.

<span class="mw-page-title-main">Luteal phase</span> The latter part of the menstrual cycle associated with ovulation and an increase in progesterone

The menstrual cycle is on average 28 days in length. It begins with menses during the follicular phase, followed by ovulation and ending with the luteal phase. Unlike the follicular phase which can vary in length among individuals, the luteal phase is typically fixed at approximately 14 days and is characterized by changes to hormone levels, such as an increase in progesterone and estrogen levels, decrease in gonadotropins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), changes to the endometrial lining to promote implantation of the fertilized egg, and development of the corpus luteum. In the absence of fertilization by sperm, the corpus luteum atrophies leading to a decrease in progesterone and estrogen, an increase in FSH and LH, and shedding of the endometrial lining (menses) to begin the menstrual cycle again.

<span class="mw-page-title-main">Cytotrophoblast</span>

"Cytotrophoblast" is the name given to both the inner layer of the trophoblast or the cells that live there. It is interior to the syncytiotrophoblast and external to the wall of the blastocyst in a developing embryo.

<span class="mw-page-title-main">Implantation (embryology)</span> First stage of pregnancy

Implantation, also known as nidation, is the stage in the embryonic development of mammals in which the blastocyst hatches, attaches, adheres, and invades into the wall of the female's uterus. Implantation is the first stage of gestation, and, when successful, the female is considered to be pregnant. An implanted embryo is detected by the presence of increased levels of human chorionic gonadotropin (hCG) in a pregnancy test. The implanted embryo will receive oxygen and nutrients in order to grow.

<span class="mw-page-title-main">Glycodelin</span> Mammalian protein found in Homo sapiens

Glycodelin(GD) also known as human placental protein-14 (PP-14)progestogen-associated endometrial protein (PAEP) or pregnancy-associated endometrial alpha-2 globulin is a glycoprotein that inhibits cell immune function and plays an essential role in the pregnancy process. In humans is encoded by the PAEP gene.

<span class="mw-page-title-main">CGB7</span> Protein-coding gene in the species Homo sapiens

Choriogonadotropin subunit beta is a protein that in humans is encoded by the CGB7 gene.

<span class="mw-page-title-main">CGB1</span> Protein-coding gene in the species Homo sapiens

Choriogonadotropin subunit beta variant 1 is a protein that in humans is encoded by the CGB1 gene.

Pinopodes are protrusions on the apical cellular membrane of uterine epithelial cells.

Hormonal regulation occurs at every stage of development. A milieu of hormones simultaneously affects development of the fetus during embryogenesis and the mother, including human chorionic gonadotropin (hCG) and progesterone (P4).

Endometrial cups form during pregnancy in mares and are the source of equine chorionic gonadotropin (eCG) and a placenta-associated structure, which is derived from the fetus. Their purpose is to increase the immunological tolerance of the mare in order to protect the developing foal.

<span class="mw-page-title-main">Maternal recognition of pregnancy</span> Crucial aspect of carrying a pregnancy to full term

Maternal recognition of pregnancy is a crucial aspect of carrying a pregnancy to full term. Without maternal recognition to maintain pregnancy, the initial messengers which stop luteolysis and promote foetal implantation, growth and uterine development finish with nothing to replace them and the pregnancy is lost.

<span class="mw-page-title-main">Neohormone</span>

Neohormones are a group of recently evolved hormones primarily associated to the success of mammalian development. These hormones are specific to mammals and are not found in other vertebrates—this is because neohormones are evolved to enhance specific mammalian functions. In males, neohormones play important roles in regulating testicular descent and preparing the sperm for internal fertilisation. In females, neohormones are essential for regulating early pregnancy, mammary gland development lactation, and viviparity. Neohormones superimpose their actions on the hypothalamic-pituitary-gonadal axis and are not associated with other core bodily functions.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000104827 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 "Entrez Gene: chorionic gonadotropin".
  4. ↑ Fiddes JC, Goodman HM (August 1980). "The cDNA for the beta-subunit of human chorionic gonadotropin suggests evolution of a gene by readthrough into the 3'-untranslated region". Nature. 286 (5774): 684–687. Bibcode:1980Natur.286..684F. doi:10.1038/286684a0. PMID   6774259. S2CID   4323775.
  5. ↑ Policastro P, Ovitt CE, Hoshina M, Fukuoka H, Boothby MR, Boime I (October 1983). "The beta subunit of human chorionic gonadotropin is encoded by multiple genes". The Journal of Biological Chemistry. 258 (19): 11492–11499. doi: 10.1016/S0021-9258(17)44254-2 . PMID   6194155.
  6. 1 2 PDB: 1HRP ​; Lapthorn AJ, Harris DC, Littlejohn A, Lustbader JW, Canfield RE, Machin KJ, et al. (June 1994). "Crystal structure of human chorionic gonadotropin". Nature. 369 (6480): 455–61. Bibcode:1994Natur.369..455L. doi:10.1038/369455a0. PMID   8202136. S2CID   4263358.
  7. ↑ "CGB3_Human". UniProt Database.
  8. ↑ "GlyGen". glygen.org. Retrieved 2023-11-27.
  9. ↑ "P0DN86". SWISS-MODEL Repository. Retrieved 2023-11-27.
  10. ↑ Cole LA (January 2015). "40 - Summary: hCG a remarkable molecule". In Cole LA, Butler SA (eds.). Human Chorionic Gonadotropin (HGC) (Second ed.). San Diego: Elsevier. pp. 411–412. doi:10.1016/b978-0-12-800749-5.00040-7. ISBN   978-0-12-800749-5.
  11. ↑ Maston GA, Ruvolo M (March 2002). "Chorionic gonadotropin has a recent origin within primates and an evolutionary history of selection". Molecular Biology and Evolution. 19 (3): 320–335. doi:10.1093/oxfordjournals.molbev.a004085. PMID   11861891.
  12. ↑ "CGB3 chorionic gonadotropin subunit beta 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2023-11-27.
  13. ↑ Rull K, Laan M (December 2005). "Expression of beta-subunit of HCG genes during normal and failed pregnancy". Human Reproduction. 20 (12): 3360–3368. doi:10.1093/humrep/dei261. PMC   1403819 . PMID   16123088.
  14. ↑ Cole LA (January 2015). "12 - Pregnancy-1, functions during preimplantation and during blastocyst implantation". In Cole LA, Butler SA (eds.). Human Chorionic Gonadotropin (HGC) (Second ed.). San Diego: Elsevier. pp. 117–123. doi:10.1016/B978-0-12-800749-5.00012-2. ISBN   978-0-12-800749-5.
  15. 1 2 Gridelet V, Perrier d'Hauterive S, Polese B, Foidart JM, Nisolle M, Geenen V (2020). "Human Chorionic Gonadotrophin: New Pleiotropic Functions for an "Old" Hormone During Pregnancy". Frontiers in Immunology. 11: 343. doi: 10.3389/fimmu.2020.00343 . PMC   7083149 . PMID   32231662.
  16. 1 2 3 Makrigiannakis A, Vrekoussis T, Zoumakis E, Kalantaridou SN, Jeschke U (June 2017). "The Role of HCG in Implantation: A Mini-Review of Molecular and Clinical Evidence". International Journal of Molecular Sciences. 18 (6): 1305. doi: 10.3390/ijms18061305 . PMC   5486126 . PMID   28629172.
  17. 1 2 Cole LA (August 2010). "Biological functions of hCG and hCG-related molecules". Reproductive Biology and Endocrinology. 8 (1): 102. doi: 10.1186/1477-7827-8-102 . PMC   2936313 . PMID   20735820.
  18. ↑ Berndt S, Perrier d'Hauterive S, Blacher S, Péqueux C, Lorquet S, Munaut C, et al. (December 2006). "Angiogenic activity of human chorionic gonadotropin through LH receptor activation on endothelial and epithelial cells of the endometrium". FASEB Journal. 20 (14): 2630–2632. doi: 10.1096/fj.06-5885fje . PMID   17065221. S2CID   20737179.
  19. ↑ "Human Chorionic Gonadotropin: Hormone, Purpose & Levels". Cleveland Clinic. Retrieved 2023-11-27.
  20. ↑ Bildik G, Akin N, Esmaeilian Y, Hela F, Yakin K, Onder T, et al. (May 2020). "hCG Improves Luteal Function and Promotes Progesterone Output through the Activation of JNK Pathway in the Luteal Granulosa Cells of the Stimulated IVF Cycles†". Biology of Reproduction. 102 (6): 1270–1280. doi: 10.1093/biolre/ioaa034 . PMID   32163131.

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