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Gene Review

ZP4  -  zona pellucida glycoprotein 4

Homo sapiens

Synonyms: ZBP, ZP1, ZPB, Zona pellucida glycoprotein 4, Zona pellucida protein B, ...
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Disease relevance of ZP4

  • Mouse lines lacking either ZP1 or ZP3 have been established with abnormal or absent zona matrices and varying degrees of infertility to examine zona structure and function in vivo [1].
  • In contrast to hZPC, the acrosome reaction induced by recombinant hZPB was not inhibited by pertussis toxin [2].
  • Zona pellucida proteins are secreted to form a filamentous zona matrix in which ZP2 and ZP3 complex into co-polymers cross-linked by ZP1 [3].
  • Sequence of complementary deoxyribonucleic acid encoding bonnet monkey (Macaca radiata) zona pellucida glycoprotein-ZP1 and its high-level expression in Escherichia coli [4].
  • In a larger panel of 75 pancreatic adenocarcinomas, these 7 MICPs (ppENK, Cyclin G, ZBP, MICP25, 27, 36, and 38) were methylated in 93, 3, 9, 15, 48, 19, and 41% of cancers, respectively, by methylation-specific PCR but not in any of 15 normal pancreata [5].

High impact information on ZP4

  • The extracellular zona pellucida surrounding mammalian eggs is formed by interactions of the ZP1, ZP2, and ZP3 glycoproteins [6].
  • The zona pellucida of mouse oocytes, composed of three major glycoproteins (ZP1, ZP2, and ZP3), performs crucial functions at fertilization and in early development [7].
  • Although the three zona proteins (ZP1, ZP2, ZP3) are well conserved, mammalian fertilization is relatively specific and human sperm do not bind to the mouse zona pellucida [8].
  • ZBP appeared to be distinct from known components of the alternative complement pathway and the classical complement system, and it did not appear to be an immunoglobulin [9].
  • Zinpyr-1 (ZP1) is a fluorescein-based bright fluorescent sensor for divalent zinc that is cell permeable without prior modification [10].

Biological context of ZP4

  • The goals of this study were to determine the effects of recombinant human ZP2, ZP3, and ZP4 on human sperm acrosomal exocytosis and sperm motility [11].
  • The amino acid sequence of the hZP1 was used to design a set of 94 (15-mer) biotinylated peptides having an overlap of 9 amino acids [12].
  • In order to define peptide epitope(s) that may be critical for eliciting an immune response sufficient to effect immunological contraception without causing any adverse effects on ovarian physiology, studies have been carried out to identify immunodominant B-cell epitopes of the ZP1 protein [12].
  • These studies, for the first time, have demonstrated that in humans, ZPB also induces acrosomal exocytosis through a Gi independent pathway [2].
  • The rZP1 also showed a sequence homology to mouse ZP1, known as a mouse orthologue of ZPB family, suggesting that the rZP2 and rZP1 are members of ZPA and ZPB families, respectively [13].

Anatomical context of ZP4

  • The mouse zona pellucida contains three glycoproteins, ZP1, ZP2, and ZP3, which are conserved in rat and human [14].
  • The expression of an additional zona glycoprotein, ZPB/4, in humans, led us to reconsider the classical mouse model of gamete interaction [15].
  • The transcript of porcine ZP1 gene was detected only in growing oocytes [16].
  • In situ hybridisation revealed that expression of ZPB was restricted to oocytes of primordial and primary follicles of adult possums; no expression was detected in the surrounding granulosa cells [17].
  • Under reducing conditions, zonae from unfertilized eggs separated into three acidic proteins with molecular weight ranges of 90,000-110,000 (ZP1), 64,000-78,000 (ZP2) and 57,000-73,000 (ZP3) [18].

Associations of ZP4 with chemical compounds

  • The open reading frame of 1,581 nt is predicted to encode a ZPB polypeptide of 527 amino acids which contains 20 cysteine residues, 7 potential N-linked glycosylation sites, a potential N-terminal signal peptide and a potential C-terminal trans-membrane domain, preceded by a furin proteolytic processing signal [17].
  • We describe here the synthesis and characterization of ZP1 sensors containing a carboxylic acid or ethyl ester functionality at the 5 or 6 position of the fluorescein [10].
  • Upon excitation of the fluorophores, coumarin 343 emission relays information concerning sensor concentration whereas ZP1 emission indicates the relative concentration of Zn2+-bound sensor [19].
  • Like the parent ZP1, both Me(2)ZP1 and Me(4)ZP1 exhibit increased fluorescence in the presence of Zn(2+) [20].
  • In each of these ZinAlkylPyr (ZAP) analogues, an alkyl group (methyl, benzyl) replaces one of the metal-binding picolyl moieties in ZP1 [21].

Other interactions of ZP4

  • Human zona pellucida glycoproteins: characterization using antibodies against recombinant non-human primate ZP1, ZP2 and ZP3 [22].
  • Under non-reduced conditions human (h) hZP1, hZP2 and hZP3 resolved as 60, 100 and 53 kDa bands respectively [22].

Analytical, diagnostic and therapeutic context of ZP4

  • Recombinant expression of human (h) ZP1, ZP2, and ZP3 produces glycoproteins that are secreted and have migration patterns in SDS-PAGE identical to those of native human zona pellucida proteins [23].
  • Using these peptides in a modified enzyme-linked immunoassay, antibodies in sera from rabbits or baboons immunized with native porcine ZP protein were screened for ZP1 peptide recognition [12].
  • The 82K antigen exhibited an estimated molecular weight of 345,000 by gel filtration chromatography in nondissociative solvent and was comprised of ZP1 and disulfide-linked heterodimers of ZP2+ZP4 and ZP3+ZP4 [24].
  • A peptide fragment reactive to 5H4 was isolated by reverse-phase HPLC from endoproteinase Lys-C-treated ZP4 glycoproteins, and its molecular mass was determined to be 7 kDa by SDS-PAGE [25].
  • METHODS:: We describe a FC method able to estimate intracellular zinc ion availability and the intracellular capability to activate a zinc signal after treatment with an NO-donor (AcOM-DEA/NO) in human PBMCs, using the fluorescent zinc-specific probe, Zinpyr-1 (ZP1), alone or in association with CD4-PE and CD8-Cychrome mAb [26].


  1. The zona pellucida: using molecular genetics to study the mammalian egg coat. Rankin, T., Dean, J. Rev. Reprod. (2000) [Pubmed]
  2. Baculovirus-expressed recombinant human zona pellucida glycoprotein-B induces acrosomal exocytosis in capacitated spermatozoa in addition to zona pellucida glycoprotein-C. Chakravarty, S., Suraj, K., Gupta, S.K. Mol. Hum. Reprod. (2005) [Pubmed]
  3. The zona pellucida "receptors". Hinsch, E., Hägele, W., Schill, W.B., Hinsch, K.D. Adv. Exp. Med. Biol. (1997) [Pubmed]
  4. Sequence of complementary deoxyribonucleic acid encoding bonnet monkey (Macaca radiata) zona pellucida glycoprotein-ZP1 and its high-level expression in Escherichia coli. Gupta, S.K., Sharma, M., Behera, A.K., Bisht, R., Kaul, R. Biol. Reprod. (1997) [Pubmed]
  5. Identification and characterization of differentially methylated CpG islands in pancreatic carcinoma. Ueki, T., Toyota, M., Skinner, H., Walter, K.M., Yeo, C.J., Issa, J.P., Hruban, R.H., Goggins, M. Cancer Res. (2001) [Pubmed]
  6. Conserved furin cleavage site not essential for secretion and integration of ZP3 into the extracellular egg coat of transgenic mice. Zhao, M., Gold, L., Ginsberg, A.M., Liang, L.F., Dean, J. Mol. Cell. Biol. (2002) [Pubmed]
  7. Oocyte-specific factors bind a conserved upstream sequence required for mouse zona pellucida promoter activity. Millar, S.E., Lader, E., Liang, L.F., Dean, J. Mol. Cell. Biol. (1991) [Pubmed]
  8. Human ZP3 restores fertility in Zp3 null mice without affecting order-specific sperm binding. Rankin, T.L., Tong, Z.B., Castle, P.E., Lee, E., Gore-Langton, R., Nelson, L.M., Dean, J. Development (1998) [Pubmed]
  9. The rabbit properdin system: I. Identification of a new factor and purification of rabbit properdin. Naff, G.B., Hedrick, S.W., Ratnoff, W.D., Novak, M.A., Smith, M.C., Steiner, C., Todd, E.W. J. Immunol. (1980) [Pubmed]
  10. Membrane-permeable and -impermeable sensors of the Zinpyr family and their application to imaging of hippocampal zinc in vivo. Woodroofe, C.C., Masalha, R., Barnes, K.R., Frederickson, C.J., Lippard, S.J. Chem. Biol. (2004) [Pubmed]
  11. Biological effects of recombinant human zona pellucida proteins on sperm function. Caballero-Campo, P., Chirinos, M., Fan, X.J., González-González, M.E., Galicia-Chavarría, M., Larrea, F., Gerton, G.L. Biol. Reprod. (2006) [Pubmed]
  12. Mapping of dominant B-cell epitopes of a human zona pellucida protein (ZP1). Skinner, S.M., Schwoebel, E.S., Prasad, S.V., Oguna, M., Dunbar, B.S. Biol. Reprod. (1999) [Pubmed]
  13. Rat zona pellucida glycoproteins: molecular cloning and characterization of the three major components. Akatsuka, K., Yoshida-Komiya, H., Tulsiani, D.R., Orgebin-Crist, M.C., Hiroi, M., Araki, Y. Mol. Reprod. Dev. (1998) [Pubmed]
  14. Human sperm do not bind to rat zonae pellucidae despite the presence of four homologous glycoproteins. Hoodbhoy, T., Joshi, S., Boja, E.S., Williams, S.A., Stanley, P., Dean, J. J. Biol. Chem. (2005) [Pubmed]
  15. Zona pellucida from fertilised human oocytes induces a voltage-dependent calcium influx and the acrosome reaction in spermatozoa, but cannot be penetrated by sperm. Patrat, C., Auer, J., Fauque, P., Leandri, R.L., Jouannet, P., Serres, C. BMC Dev. Biol. (2006) [Pubmed]
  16. Cloning of a cDNA coding for porcine zona pellucida glycoprotein ZP1 and its genomic organization. Taya, T., Yamasaki, N., Tsubamoto, H., Hasegawa, A., Koyama, K. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  17. Isolation and characterisation of a cDNA encoding a zona pellucida protein (ZPB) from the marsupial Trichosurus vulpecula (brushtail possum). Haines, B.P., Rathjen, P.D., Hope, R.M., Whyatt, L.M., Holland, M.K., Breed, W.G. Mol. Reprod. Dev. (1999) [Pubmed]
  18. Characterization of the human zona pellucida from fertilized and unfertilized eggs. Shabanowitz, R.B., O'Rand, M.G. J. Reprod. Fertil. (1988) [Pubmed]
  19. Esterase-activated two-fluorophore system for ratiometric sensing of biological zinc(II). Woodroofe, C.C., Won, A.C., Lippard, S.J. Inorganic chemistry. (2005) [Pubmed]
  20. 6-methylpyridyl for pyridyl substitution tunes the properties of fluorescent zinc sensors of the Zinpyr family. Goldsmith, C.R., Lippard, S.J. Inorganic chemistry. (2006) [Pubmed]
  21. Analogues of zinpyr-1 provide insight into the mechanism of zinc sensing. Goldsmith, C.R., Lippard, S.J. Inorganic chemistry. (2006) [Pubmed]
  22. Human zona pellucida glycoproteins: characterization using antibodies against recombinant non-human primate ZP1, ZP2 and ZP3. Gupta, S.K., Yurewicz, E.C., Sacco, A.G., Kaul, R., Jethanandani, P., Govind, C.K. Mol. Hum. Reprod. (1998) [Pubmed]
  23. Proteolytic processing of human zona pellucida proteins. Kiefer, S.M., Saling, P. Biol. Reprod. (2002) [Pubmed]
  24. Pathways to immunocontraception: biochemical and immunological properties of glycoprotein antigens of the porcine zona pellucida. Yurewicz, E.C., Sacco, A.G., Subramanian, M.G. Adv. Exp. Med. Biol. (1986) [Pubmed]
  25. Blocking of human sperm-zona interaction by monoclonal antibodies to a glycoprotein family (ZP4) of porcine zona pellucida. Koyama, K., Hasegawa, A., Inoue, M., Isojima, S. Biol. Reprod. (1991) [Pubmed]
  26. Single and three-color flow cytometry assay for intracellular zinc ion availability in human lymphocytes with Zinpyr-1 and double immunofluorescence: Relationship with metallothioneins. Malavolta, M., Costarelli, L., Giacconi, R., Muti, E., Bernardini, G., Tesei, S., Cipriano, C., Mocchegiani, E. Cytometry. Part A : the journal of the International Society for Analytical Cytology. (2006) [Pubmed]
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