ZP3

Last updated
ZP3
Zp3 structure pdb 3nk3.png
Identifiers
Aliases ZP3 , ZP3A, ZP3B, ZPC, Zp-3, zona pellucida glycoprotein 3 (sperm receptor), zona pellucida glycoprotein 3, OOMD3
External IDs OMIM: 182889; MGI: 99215; HomoloGene: 5178; GeneCards: ZP3; OMA:ZP3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_007155
NM_001110354

NM_011776

RefSeq (protein)

NP_001103824
NP_009086

NP_035906

Location (UCSC) Chr 7: 76.4 – 76.44 Mb Chr 5: 136.01 – 136.02 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Zona pellucida sperm-binding protein 3, also known as zona pellucida glycoprotein 3 (Zp-3) or the sperm receptor, is a ZP module-containing protein that in humans is encoded by the ZP3 gene. [5] ZP3 is the glycoprotein in the zona pellucida most important for inducting the acrosome reaction of sperm cells at the beginning of fertilization. [6]

Contents

Function

The zona pellucida (ZP) is a specialized extracellular matrix that surrounds the oocyte and early embryo. It is composed of three or four glycoproteins (ZP1-4) with various functions during oogenesis, fertilization and preimplantation development. The protein encoded by this gene is a major structural component of the ZP and functions in primary binding and stimulation of the sperm acrosome reaction. The nascent protein contains a N-terminal signal peptide sequence, a conserved "ZP domain" module, a consensus furin cleavage site (CFCS), a polymerization-blocking external hydrophobic patch (EHP), and a C-terminal transmembrane domain. Cleavage at the CFCS separates the mature protein from the EHP, allowing it to incorporate into nascent ZP filaments. A variation in the last exon of this gene has previously served as the basis for an additional ZP3 locus; however, sequence and literature review reveals that there is only one full-length ZP3 locus in the human genome. Another locus encoding a bipartite transcript designated POMZP3 contains a duplication of the last four exons of ZP3, including the above described variation, and maps closely to this gene. [5]

In mice, ZP3 (more specifically the portion in its exon 7) is the single ZP protein that is sufficient and necessary for sperm binding in vitro, [6] but is insufficient for fertilization in vivo. [7] In humans, ZP1, ZP3, and ZP4 all appear partially responsible for starting the acrosome reaction. [8]

Orthologs of these genes are found throughout Vertebrata. The western clawed frog appears to have two orthologs, and the sea lamprey has seven. [9]

3D Structure

X-ray crystallographic studies of the N-terminal half of mammalian ZP3 ( PDB: 3D4C, 3D4G, 3EF7, 5OSQ ) [10] as well as its full-length avian homolog ( PDB: 3NK3, 3NK4 ) [11] revealed that the protein's ZP module consists of two immunoglobulin-like domains, ZP-N and ZP-C. The latter, which contains EHP as well as a ZP3-specific subdomain, interacts with the ZP-N domain of a second molecule to generate an antiparallel homodimeric arrangement required for protein secretion. [11]

Mutations

The Zona Pellucida (ZP) is a complex matrix of glycoprotein that surrounds the oocyte and plays a crucial role in the attachment of sperm during reproduction. Ultimately, through the facilitation of sperm binding and the initiation of the acrosome reaction, the ZP proteins are essential to reproduction and have an important impact on fertility. Research through the Journal of Cellular and Molecular Medicine conducted experiments to determine the mechanisms surrounding possible mutations to the ZP gene and how they would impact fertility. [12] By performing whole-exome sequencing they isolated a genome that had a mutation in the ZP3 and the ZP1 genes. They then transfected these genes into HeLa cell cultures and ran a variety of tests to isolate the consequences of these mutations. The authors wrote this regarding their results:

“The results indicate that the mutations are involved in the reduced secretion of ZP1 and ZP3 and leading to connection failure of the ZP filaments in vitro. The data suggest a potential that the mutations may be involved in the lacking ZP phenotype, which need to be further investigated in vivo.” (Cao, Qiqi, et al.)

It is clear that the ZP proteins are crucial to expressing a correct ZP phenotype in humans, in which all of the ZP proteins 1-4 are properly functioning. Without this interface of proper protein function, sperm binding is inhibited, and fertility is compromised.

Related Research Articles

<span class="mw-page-title-main">Acrosome reaction</span> Sperm-meets-egg process

For fertilization to happen between a sperm and egg cell, a sperm must first fuse with the plasma membrane and then penetrate the female egg cell to fertilize it. While the fusion of the sperm cell with the egg cell's plasma membrane is relatively straightforward, penetrating the egg's protective layers, such as the zona pellucida, presents a significant challenge. Therefore, sperm cells go through a process known as the acrosome reaction, which is the reaction that occurs in the acrosome of the sperm as it approaches the egg.

<span class="mw-page-title-main">Zona pellucida</span> Glycoprotein layer surrounding the plasma membrane of mammalian oocytes

The zona pellucida is the specialized area surrounding mammalian oocytes (eggs). It is also known as an egg coat. The zona pellucida is essential for oocyte growth and fertilization.

Hyperactivation is a type of sperm motility. Hyperactivated sperm motility is characterised by a high amplitude, asymmetrical beating pattern of the sperm tail (flagellum). This type of motility may aid in sperm penetration of the zona pellucida, which encloses the ovum.

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

Acrosin is a digestive enzyme that acts as a protease. In humans, acrosin is encoded by the ACR gene. Acrosin is released from the acrosome of spermatozoa as a consequence of the acrosome reaction. It aids in the penetration of the Zona Pellucida.

<span class="mw-page-title-main">Human fertilization</span> Union of a human egg and sperm

Human fertilization is the union of an egg and sperm, occurring primarily in the ampulla of the fallopian tube. The result of this union leads to the production of a fertilized egg called a zygote, initiating embryonic development. Scientists discovered the dynamics of human fertilization in the 19th century.

<span class="mw-page-title-main">Cortical reaction</span> Biological process that prevents polyspermy

The cortical reaction is a process initiated during fertilization that prevents polyspermy, the fusion of multiple sperm with one egg. In contrast to the fast block of polyspermy which immediately but temporarily blocks additional sperm from fertilizing the egg, the cortical reaction gradually establishes a permanent barrier to sperm entry and functions as the main part of the slow block of polyspermy in many animals.

The vitelline membrane or vitelline envelope is a structure surrounding the outer surface of the plasma membrane of an ovum or, in some animals, the extracellular yolk and the oolemma. It is composed mostly of protein fibers, with protein receptors needed for sperm binding which, in turn, are bound to sperm plasma membrane receptors. The species-specificity between these receptors contributes to prevention of breeding between different species. It is called zona pellucida in mammals. Between the vitelline membrane and the oolemma is a fluid-filled perivitelline space.

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

Uromodulin (UMOD), also known as Tamm–Horsfall protein (THP), is a zona pellucida-like domain-containing glycoprotein that in humans is encoded by the UMOD gene. Uromodulin is the most abundant protein excreted in ordinary urine.

Sialyl-Lewis <sup>X</sup> Chemical compound

Sialyl LewisX (sLeX), also known as cluster of differentiation 15s (CD15s) or stage-specific embryonic antigen 1 (SSEA-1), is a tetrasaccharide carbohydrate which is usually attached to O-glycans on the surface of cells. It is known to play a vital role in cell-to-cell recognition processes. It is also the means by which an egg attracts sperm; first, to stick to it, then bond with it and eventually form a zygote.

Immunocontraception is the use of an animal's immune system to prevent it from fertilizing offspring. Contraceptives of this type are not currently approved for human use.

<span class="mw-page-title-main">SPA17</span> Protein-coding gene in the species Homo sapiens

Sperm surface protein Sp17 is a protein that in humans is encoded by the SPA17 gene.

<span class="mw-page-title-main">ZP2</span> Protein-coding gene in the species Homo sapiens

Zona pellucida sperm-binding protein 2 is a protein that in humans is encoded by the ZP2 gene.

<span class="mw-page-title-main">SPAM1</span> Enzyme

Hyaluronidase PH-20 is an enzyme that in humans is encoded by the SPAM1 gene.

<span class="mw-page-title-main">ZP4</span> Protein-coding gene in the species Homo sapiens

Zona pellucida sperm-binding protein 4, ZP-4 or avilesine, named after its discoverer Manuel Avilés Sánchez is a protein that in humans is encoded by the ZP4 gene.

<span class="mw-page-title-main">Sperm-associated antigen 8</span> Protein-coding gene in the species Homo sapiens

Sperm-associated antigen 8 is a protein that in humans is encoded by the SPAG8 gene.

The zona pellucida-like domain is a large protein region of about 260 amino acids. It has been recognised in a variety of receptor-like eukaryotic glycoproteins. All of these molecules are mosaic proteins with a large extracellular region composed of various domains, often followed by either a transmembrane domain and a short cytoplasmic region or by a GPI-anchor.

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

Folliculogenesis-specific basic helix-loop-helix, also known as factor in the germline alpha (FIGalpha) or transcription factor FIGa, is a protein that in humans is encoded by the FIGLA gene. The FIGLA gene is a germ cell-specific transcription factor preferentially expressed in oocytes that can be found on human chromosome 2p13.3.

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

Juno also known as folate receptor 4, folate receptor delta or IZUMO1R is a protein that in humans is encoded by the FOLR4 gene. Juno is a member of the folate receptor family and is GPI-anchored to the plasmalemma of the mammalian egg cell that recognizes its sperm-riding counterpart, IZUMO1, and facilitates fertilization. The protein was named after Juno, the Roman goddess of fertility and marriage.

A disintegrin and metalloprotease 3, or ADAM3, belongs to a family of peptidase proteins referred to as ADAMs. Many of these are solely found in spermatogenic cells, specifically in the anterior portion of capacitated spermatozoa heads. This membrane protein is critical for crucial steps in fertilization such as migration of sperm through the uterus to the oviduct as well as binding to the zona pellucida. Inactivation of ADAM3 is a cause of male infertility.

Paul Michael Wassarman is an American biologist who has been Professor in the Dept. of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai since 1996. His laboratory identified and characterised proteins that make up the zona pellucida (ZP) of mammalian eggs and determined their role in fertilisation.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000188372 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000004948 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: zona pellucida glycoprotein 3 (sperm receptor)".
  6. 1 2 Litscher, E. S.; Williams, Z.; Wassarman, P. M. (2009). "Zona pellucida glycoprotein ZP3 and fertilization in mammals". Molecular Reproduction and Development. 76 (10): 933–941. doi:10.1002/mrd.21046. PMID   19504560. S2CID   21186053.
  7. Avella MA, Baibakov B, Dean J (2014). "A single domain of the ZP2 zona pellucida protein mediates gamete recognition in mice and humans". J Cell Biol. 205 (6): 801–809. doi:10.1083/jcb.201404025. PMC   4068139 . PMID   24934154. Female mice that form a zona pellucida lacking ZP2 are sterile
  8. Gupta, SK; Bhandari, B (January 2011). "Acrosome reaction: relevance of zona pellucida glycoproteins". Asian Journal of Andrology. 13 (1): 97–105. doi:10.1038/aja.2010.72. PMC   3739397 . PMID   21042299.
  9. "EggNOG Database | Orthology predictions and functional annotation". eggnogdb.embl.de. Archived from the original on 4 March 2019. Retrieved 5 March 2019.
  10. Monné M, Han L, Schwend T, Burendahl S, Jovine L (2008). "Crystal structure of the ZP-N domain of ZP3 reveals the core fold of animal egg coats". Nature. 456 (7222): 653–7. Bibcode:2008Natur.456..653M. doi:10.1038/nature07599. hdl: 11563/8930 . PMID   19052627. S2CID   4430083. PDB: 3D4C, 3D4G, 3EF7
  11. 1 2 Han L, Monné M, Okumura H, Schwend T, Cherry AL, Flot D, Matsuda T, Jovine L (2010). "Insights into egg coat assembly and egg-sperm interaction from the X-ray structure of full-length ZP3". Cell. 143 (3): 404–15. doi: 10.1016/j.cell.2010.09.041 . hdl: 11563/8931 . PMID   20970175. S2CID   18583237. PDB: 3NK3, 3NK4
  12. Cao, Qiqi; Zhao, Chun; Zhang, Xiaolan; Zhang, Heng; Lu, Qianneng; Wang, Congjing; Hu, Yue; Ling, Xiufeng; Zhang, Junqiang; Huo, Ran (2020-06-22). "Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human". Journal of Cellular and Molecular Medicine. 24 (15): 8557–8566. doi:10.1111/jcmm.15482. ISSN   1582-1838. PMC   7412702 . PMID   32573113.

[1]

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


  1. Cao, Qiqi, et al. “Heterozygous Mutations in ZP1 and ZP3 Cause Formation ...” Journal of Cellular and Molecular Medicine, Wiley Online Library, 22 June 2020, onlinelibrary.wiley.com/doi/10.1111/jcmm.15482.