The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three (mouse) or four (human) glycoproteins (ZP1-4) with various functions during fertilization and preimplantation development. The protein encoded by this gene is a structural component of the zona pellucida and functions in secondary binding and penetration of acrosome-reacted spermatozoa. The nascent protein contains a N-terminalsignal peptide sequence, a conserved ZP domain, a consensus furin cleavage site, and a C-terminal transmembrane domain. It is hypothesized that furin cleavage results in release of the mature protein from the plasma membrane for subsequent incorporation into the zona pellucida matrix. However, the requirement for furin cleavage in this process remains controversial based on mouse studies.[2]
The sperm-binding domain on the ZP2 protein is necessary in both humans and mice for oocyte-sperm recognition and penetration of the zona pellucida. It is also responsible for the primary block to polyspermy in mammals. The oocyte has cortical granules peripherally located under the cortex that contain a proteolytic protein called ovastacin. After the sperm binds to ZP2, the cortical granules are exocytosed releasing ovastacin into the perivitelline space. Ovastacin cleaves ZP2 at the N terminus, preventing more sperm from binding and penetrating the oocyte, thus hardening the zona pellucida. Ovastacin is only found in oocytes, and is part of the astacin family of metalloendoproteases. Female mice engineered without ovastacin showed that ZP2 was not cleaved after fertilization.[3][4]
3D structure
The crystal structure of the sperm-binding domain of ZP2 at 0.95 Å resolution (PDB: 5II6)[5] showed that is shares the same ZP-N fold first identified in structures of ZP3 (PDB: 3D4C, 3D4G, 3EF7, 3NK3, 3NK4).[6][7] This provided experimental evidence for the suggestion that the N-terminal region of ZP2 consists of three ZP-N repeats [6][8] and revealed that - despite insignificant sequence identity - ZP2 is structurally similar to VERL, the vitelline envelope receptor for egg lysin of the mollusk abalone (PDB: 5II4, 5II5, 5MR2, 5IIC, 5IIA, 5IIB, 5MR3). This established a link between invertebrate and vertebrate fertilization by suggesting that, despite being separated by 600 million years of evolution, mollusk and human use a common protein fold to interact with sperm.[5]
References
↑Liang LF, Dean J (Apr 1993). "Conservation of mammalian secondary sperm receptor genes enables the promoter of the human gene to function in mouse oocytes". Dev Biol. 156 (2): 399–408. doi:10.1006/dbio.1993.1087. PMID8385033.
↑ 6.06.1Monné 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. doi:10.1038/nature07599. PMID19052627. PDB: 3D4C, 3D4G, 3EF7
↑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. PMID20970175. PDB: 3NK3, 3NK4
↑Callebaut I, Mornon JP, Monget P (2007). "Isolated ZP-N domains constitute the N-terminal extensions of Zona Pellucida proteins". Bioinformatics. 23: 1871–1874. doi:10.1093/bioinformatics/btm265. PMID17510169.
Further reading
Rankin T, Dean J (2000). "The zona pellucida: using molecular genetics to study the mammalian egg coat". Rev. Reprod. 5 (2): 114–121. doi:10.1530/ror.0.0050114. PMID10864856.
Mori T, Guo MW, Sato E, Baba T, Takasaki S, Mori E (2000). "Molecular and immunological approaches to mammalian fertilization". J. Reprod. Immunol. 47 (2): 139–158. doi:10.1016/S0165-0378(00)00055-3. PMID10924747.
Loftus BJ, Kim UJ, Sneddon VP, Kalush F, Brandon R, Fuhrmann J, Mason T, Crosby ML, Barnstead M, Cronin L, Deslattes Mays A, Cao Y, Xu RX, Kang HL, Mitchell S, Eichler EE, Harris PC, Venter JC, Adams MD (1999). "Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q". Genomics. 60 (3): 295–308. doi:10.1006/geno.1999.5927. PMID10493829.
Tsubamoto H, Hasegawa A, Nakata Y, Naito S, Yamasaki N, Koyama K (1999). "Expression of recombinant human zona pellucida protein 2 and its binding capacity to spermatozoa". Biol. Reprod. 61 (6): 1649–1654. doi:10.1095/biolreprod61.6.1649. PMID10570015.
Howes E, Pascall JC, Engel W, Jones R (2002). "Interactions between mouse ZP2 glycoprotein and proacrosin; a mechanism for secondary binding of sperm to the zona pellucida during fertilization". J. Cell Sci. 114 (Pt 22): 4127–36. PMID11739644.
Tanii I, Oh-oka T, Yoshinaga K, Toshimori K (2002). "A mouse acrosomal cortical matrix protein, MC41, has ZP2-binding activity and forms a complex with a 75-kDa serine protease". Dev. Biol. 238 (2): 332–341. doi:10.1006/dbio.2001.0380. PMID11784014.
Rankin TL, Coleman JS, Epifano O, Hoodbhoy T, Turner SG, Castle PE, Lee E, Gore-Langton R, Dean J (2003). "Fertility and taxon-specific sperm binding persist after replacement of mouse sperm receptors with human homologs". Dev. Cell. 5 (1): 33–43. doi:10.1016/S1534-5807(03)00195-3. PMID12852850.
Hinsch E, Groeger S, Oehninger S, Hinsch KD (2003). "Localization and functional importance of a conserved zona pellucida 2 protein domain in the human and bovine ovary using monoclonal anti-ZP2 peptide antibodies". Theriogenology. 60 (7): 1331–1344. doi:10.1016/S0093-691X(03)00169-9. PMID14511786.
Furlong LI, Harris JD, Vazquez-Levin MH (2006). "Binding of recombinant human proacrosin/acrosin to zona pellucida (ZP) glycoproteins. I. Studies with recombinant human ZPA, ZPB, and ZPC". Fertil. Steril. 83 (6): 1780–1790. doi:10.1016/j.fertnstert.2004.12.042. PMID15950651.
Caballero-Campo P, Chirinos M, Fan XJ, González-González ME, Galicia-Chavarría M, Larrea F, Gerton GL (2006). "Biological effects of recombinant human zona pellucida proteins on sperm function". Biol. Reprod. 74 (4): 760–768. doi:10.1095/biolreprod.105.047522. PMID16407501.
