Glycodelin is found in oocyte and sperm

January 4, 2024
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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.

Human endometrium synthesizes several proteins under the influence of progesterone. Of these proteins, glycodelin is of particular interest. It is synthesized by the endometrial glands in the luteal phase of menstrual cycle.

The temporal and spatial expression of GD in the female reproductive tract combined with its biological activities suggest that this glycoprotein probably plays an essential physiological role in the regulation of fertilization, implantation and maintenance of pregnancy.

Structure

22 N-terminal amino acid sequence

Glycodelin is codified by 180 amino acid but it is thought that 18 of these are supposed signals peptides. The molecular weight of GD is 20,555, while its mature form is estimated to weigh 18,787. It is encoded by a 1-kilobase-pair mRNA that is expressed in human secretory endometrium and decidua but not in postmenopausal endometrium, placenta, liver, kidney, and adrenals. The four cysteinyl residues (positions 66, 106, 119, and 160) responsible for intramolecular disulfide bridges in lactoglobulins are all conserved in GD. Southern blot analysis of human DNA suggested that GD gene sequences compass some 20 kilobase pairs of the human genomic DNA.

N-terminal amino acid sequence

PAEP gene structure
PAEP gene structure

The N-terminal amino acid sequence of glycodelin is M D I P Q T K Q D L E L P K L A G T W H S M. This sequence can be compared with horse, sheep, goat, bovine and buffalo beta-lactoglobulin. For example, there are 13 identities out of 22 possible matches with horse beta-lactoglobulin.

β-Lactoglobulin (BLG) is the major whey protein of cow and sheep‘s milk (~3 g/L), and is also present in many other mammalian species; a notable exception being humans. Its structure, properties and biological role have been reviewed many times. BLG is considered to be a milk allergen. The major protein in whey is β-lactoglobulin, followed by α-lactalbumin (β-lactoglobulin ≈⁠ ⁠65%, α-lactalbumin ≈⁠⁠ ⁠25%, serum albumin ≈⁠⁠ ⁠8%, other ≈⁠ ⁠2%). β-lactoglobulin is a lipocalin protein, and can bind many hydrophobic molecules, suggesting a role in their transport. β-lactoglobulin has also been shown to be able to bind iron via siderophores and thus might have a role in combating pathogens. Upon ingestion BLG is able to shuttle complexed iron into human immune cells, thereby providing micronutrition to these cells and participating in immune tolerance. A homologue of β-lactoglobulin is lacking in human breast milk.

 β-lactoglobulin is of direct interest to the food industry since its properties can variously be advantageous or disadvantageous in dairy products and processing. Though β-lactoglobulin is considered a major allergen, the protective impact of the consumption of raw milk has been shown to dependent on the protein-content of the whey fraction and thus of β-lactoglobulin. This great contrast, on the one hand an allergen and on the other protective, has now been linked with its ability to carry micronutrient. When β-lactoglobulin carried micronutrient it acted tolerogenic and protected against allergy development. However, when the loading was missing, it turned into an allergen. Laboratory polymerization of β-lactoglobulin by microbial transglutaminase reduces its allergenicity in children and adults with an IgE-mediated cow’s milk allergy. Bovine β-lactoglobulin is a relatively small protein of 162 residues, with an 18.4 kDa. In physiological conditions it is predominantly dimeric, but dissociates to a monomer below about pH 3, preserving its native state as determined by using NMR. Conversely, β-lactoglobulin also occurs in tetrameric, octameric and other multimeric aggregation forms under a variety of natural conditions. In 2018 it was announced that genetically modified cows were grown. The cows had their β-Lactoglobulin producing genes removed by a zygote-mediated deletion process. See also: Caseine

PAEP gene

This gene is a member of the kernel lipocalin superfamily whose members share relatively low sequence similarity but have highly conserved exon-intron structure and three-dimensional protein folding. The PAEP gene is clustered on the long arm of chromosome 9 and encodes for GD protein. It is mainly expressed in 60 organs, but reaches its highest expression level in the decidua (defined as thick layer of modified mucous membrane which lines the uterus during pregnancy and is shed with the afterbirth, also modified mucosal lining of the uterus (that is, modified endometrium) that forms every month, in preparation for pregnancy).

Function

GD is the most important protein secreted in the endometrium during the mid-luteal phase of the menstrual cycle and during the first semester of pregnancy. Four distinct forms of glycoprotein, with identical protein backbones but different glycosylation profiles, are found in amniotic fluid, follicular fluid and seminal plasma of the reproductive system. These glycoproteins have distinct and essential roles in regulating a uterine environment suitable for pregnancy and in the timing and occurrence of the appropriate sequence of events in the fertilization process.

Glycodelin-A

In the female genital tract is mainly expressed in EECs (cultured endometrial epithelial cells) and secreted into the amniotic fluid, endometrium/decidua and maternal serum. Glycodelin-A has contraceptive and immunosuppressive functions, due to the fact that suppresses Natural Killer cells, achieving the prevention of the maternal rejection of the fetus at the fetomaternal interface. It has a molecular weight of 18.78 KDa determined from the cDNA sequence.

Glycodelin-S

Is secreted from seminal vesicles to the seminal fluid. A number of alternatively spliced transcript variants have been observed at this locus, but the full-length nature of only two, each encoding the same protein, has been determined. During the passage of the sperm through the cervix, glycodelin S is de-glycosylated and dissociates from the sperm, allowing the sperm to mature.

Glycodelin-F

Is secreted by granulosa cells into the follicular fluid. Glycodelin-F reduces the blinding of spermatozoa to the zona pellucida which is mainly expressed in the ovary, and synthesised in the granulosa cells, has a function in principle similar to that of Glycodelin-A. It also binds the sperm head, thereby inhibiting acrosome reaction and sperm-egg binding. Upon de-glycosilation, glycodelin F dissociates from the sperm and sperm-egg binding is possible. The de-glycosilation takes place during the passage of the sperm through the corona cell layer. Glycodelin F is thereby important to prevent a premature acrosome reaction.

Glycodelin-C

Found in Cumulus Oophorus, stimulates binding of the spermatozoa to the zona pellucida. First, cumulus cells reduce the spermatozoa-zona binding inhibitory activity of follicular fluid probably by taking up and converting glycodelin-A and glycodelin-F into glycodelin-C. Second, spermatozoa have enhanced zona binding ability after penetrating through the cumulus oophorus. (Cumulus oophorus means “egg-bearing little cloud.” As a sperm enters the cumulus oophorus, the enzyme hyaluronidase on the sperm head dissolves hyaluronic acid, a major component of the cementing material found between the cells of the cumulus oophorus as well as between other cells in the body.) Glycodelin-C is responsible for the latter observation.

GLYCOFORMSOURCEGLYCOSYLATIONREPRODUCTIVE FUNCTIONS
GdAAmniotic fluid, pregnancy deciduaHigh sialylation, more fucosylationImmunoprotection for implantation and placentation, antifertilizing, inhibiting spermatozoa-zona pellucida binding
GdSSeminal plasma, seminal vesiclesNo sialylated glycans, rich in fucose and mannosePreventing premature capacitation
GdFOvarian follicles, oviductFucosylated Lewis-x and Lewis-y, more N-acetylglucosamineInhibiting spermatozoa-zona pellucida, preventing premature acrosome reaction
GdCCumulus oophorus, converted from GdA and GdFReacting with specific agglutinins in lectin-binding mannerStimulating spermatozoa-zona pellucida binding

Sialylation refers to the terminal addition of sialic acid units to oligosaccharides and glycoproteins. Sialylation of glycoproteins and glycopilids finds role in embryonic development, neurodevelopment, reprogramming, oncogenesis, and immune responses. It has recently reported of role in cell fate decision during development, reprogramming, and cancer progression.

  • Sialyation at ScienceDirect
  • Li, F., Ding, J. Sialylation is involved in cell fate decision during development, reprogramming and cancer progression. Protein Cell 10, 550–565 (2019). https://doi.org/10.1007/s13238-018-0597-5

Fucosylation is the process of transferring fucose from GDP-fucose to their substrates, which includes certain proteins, N- and O-linked glycans in glycoprotein or glycolipids, by fucosyltransferases in all mammalian cells. Fucosylated glycans play vital role in selectin-mediated leukocyte extravasation, lymphocyte homing, and pathogen–host interactions, whereas fucosylated proteins are essential for signaling transduction in numerous ontogenic events. Aberrant fucosylation due to the availability of high energy donor GDP-fucose, abnormal expression of FUTs and/or α-fucosidase, and the availability of their substrates leads to different fucosylated glycan or protein structures. Accumulating evidence demonstrates that aberrant fucosylation plays important role in all aspects of cancer biology.

Fucose is a hexose deoxy sugar with the chemical formula C6H12O5. It is found on N-linked glycans on the mammalian, insect and plant cell surface. Fucose is the fundamental sub-unit of the seaweed polysaccharide fucoidan. The α(1→3) linked core of fucoidan is a suspected carbohydrate antigen for IgE-mediated allergy. Two structural features distinguish fucose from other six-carbon sugars present in mammals: the lack of a hydroxyl group on the carbon at the 6-position (C-6) (thereby making it a deoxy sugar) and the L-configuration. It is equivalent to 6-deoxy-l-galactose. In the fucose-containing glycan structures, fucosylated glycans, fucose can exist as a terminal modification or serve as an attachment point for adding other sugars. In human N-linked glycans, fucose is most commonly linked α-1,6 to the reducing terminal β-N-acetylglucosamine. However, fucose at the non-reducing termini linked α-1,2 to galactose forms the H antigen, the substructure of the A and B blood group antigens.

H antigen (“H substance” redirects here). The term also historically referred to histamine. H antigen can refer to one of various types of antigens having diverse biological functions:

Fucose is released from fucose-containing polymers by an enzyme called α-fucosidase found in lysosomes. l-Fucose has several potential applications in cosmetics, pharmaceuticals, and dietary supplements Fucosylation of antibodies has been established to reduce binding to the Fc receptor of Natural Killer cells and thereby reduce antigen-dependent cellular cytotoxicity. Therefore, afucosylated monoclonal antibodies have been designed to recruit the immune system to cancers cells have been manufactured in cell lines deficient in the enzyme for core fucosylation (FUT8), thereby enhancing the in vivo cell killing.

Level concentrations

PP-14 is found in the oocyte and in the sperm. In men, the concentration of this protein in seminal plasma is higher than those in serum. In women, the levels in follicular fluid exceed those of non-pregnant women.

·Seminal plasma:

PP-14 is a significant protein constituent in most seminal plasma samples of men; sometimes comprising over 2.5% of the total protein content. The concentration of PP-14 in seminal plasma from men with oligospermia is in the reference range of this protein derived from values measured in normal men. However, vasectomized men concentrations are less than normal.

  • Bolton, A. E.; Pinto-Furtado, L. G.; Andrew, C. E.; Chapman, M. G. (June 1986). “Measurement of the pregnancy-associated proteins, placental protein 14 and pregnancy-associated plasma protein A in human seminal plasma”. Clinical Reproduction and Fertility. 4 (3): 233–240. ISSN 0725-556X. PMID 2427179.

·Women’s tissues and body fluids:

In serum of non-pregnant women, the concentration of PP-14 is approximately 15-40 µg/L.

In normal pregnancy:

Location (tissues and body fluids)PP-14 concentrations (approximately)Time
SerumUp to 2200 µg/L (highest)6–12 weeks
—Decreasing concentrationsAfter 16 weeks
—200 µg/L approx.24 weeks (plateaued)
Amniotic fluid232 mg/L (highest) (higher than those in maternal serum throughout pregnancy)12–20 weeks
Cord blood15-22 µg or undetectable————
Early pregnancy decidua41–160 mg/g total protein————
Late pregnancy decidua60-2700 µg/g total protein————
Amnion and chorion laeveFrom 50 to 750 µg/g protein————
From 50 to 1000 µg/g protein————
Early pregnancy placenta0.25–15 mg/g————
Late pregnancy placenta3-430 µg/g protein————

The concentrations of PP-14 in pregnancy serum are comparable with hCG (Human Chorionic Gonadotropin). Among all the placental proteins, the amniotic fluid PP-14 concentration is the most outstanding as decidua is a source of this protein.

  • JULKUNEN, MERVI; RUTANEN, EEVA-MARJA; KOSKIMIES, AARNE; RANTA, TAPIO; BOHN, HANS; SEPPALA, MARKKU (November 1985). “Distribution of placental protein 14 in tissues and body fluids during pregnancy”. BJOG: An International Journal of Obstetrics and Gynaecology. 92 (11): 1145–1151. doi:10.1111/j.1471-0528.1985.tb03027.x. ISSN 1470-0328. PMID 4063232. S2CID 40266453.

Future clinical applications

Placental Protein 14 has some clinical applications:

1. Biomarker of premature rupture of membranes

Premature rupture of membranes is a common pregnancy complication, taking into account that the current method does not satisfy the medical community, some researches have determined a new method: the analysis of placental protein in the maternal plasma and vaginal fluid. The results of these studies have shown that PP-14’s concentration increased in the case of premature rupture of membranes. So this study conclude that PP-14 is an excellent biomarker with a sensibility of 100% and a specificity of 87,5%.

2. Biomarker in in vitro fertilization process

PP-14 is known to be a great marker to predict the outcome of in vitro fertilization and the embryo transfer cycle. Some studies have shown that the serum concentration of Placental Protein 14 was highly increased after the embryo transfer cycle, and they conclude that PP-14 might be an excellent marker to predict the endometrial receptivity.

References

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