Zona pellucida-like domain explained

The zona pellucida-like domain (ZP domain / ZP-like domain / ZP module)^{[1] [2]} is a large protein region of about 260 amino acids. It has been recognised in a variety of receptor-like eukaryotic glycoproteins.^[1] 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.^[2]

Functional and crystallographic studies revealed that the "ZP domain" region common to all these proteins is a protein polymerization module that consists of two distinct but structurally related immunoglobulin-like domains, ZP-N and ZP-C, separated by an interdomain linker (ITD).^{[3] [4] [5] [6] [7] [8] [9]} The ZP module is located in the C-terminal portion of the extracellular region and – with the exception of non-polymeric family member ENG^[10] – contains 8 or 10 conserved Cys residues involved in disulfide bonds.^{[4] [5] [8]} The ZP-C domain contains a EHP/IHP motif that controls polymerization.^[11]

The first 3D structure of a homopolymeric ZP module protein filament, native human uromodulin (UMOD), was determined by cryo-EM.^{[12] [13]}

Additional copies of isolated ZP-N domains are found in the N-terminal region of egg coat protein subunits involved in fertilization in both vertebrates and invertebrates, with the human zona pellucida components ZP1, ZP2 and ZP4 being the best understood.^{[4] [14]} The mollusc "vitelline envelope receptor for egg lysin" (VERL,) is found in the vitelline envelope of mollusc eggs and consists of 22 VERL repeats followed by a ZP module. Structural work from 2017 demonstrated that VERL repeats are also ZP-N domains.^[15]

Examples

Humans genes encoding proteins containing this domain include:

• CUZD1
• DMBT1
• ENG
• GP2
• OIT3
• POMZP3
• TECTA, TECTB, TGFBR3
• UMOD, UMODL1
• ZP1, ZP2, ZP3, ZP4, ZPLD1

Notes and References

1. Bork P, Sander C . A large domain common to sperm receptors (Zp2 and Zp3) and TGF-beta type III receptor . FEBS Lett. . 300 . 3 . 237–40 . 1992 . 1313375 . 10.1016/0014-5793(92)80853-9. 38778076 . free .
2. Jovine L, Darie CC, Litscher ES, Wassarman PM . Zona pellucida domain proteins . Annu. Rev. Biochem. . 74 . 83–114 . 2005 . 15952882 . 10.1146/annurev.biochem.74.082803.133039.
3. Jovine L, Qi H, Williams Z, Litscher E, Wassarman PM . The ZP domain is a conserved module for polymerization of extracellular proteins . Nat. Cell Biol. . 4 . 6 . 457–61 . 2002 . 12021773 . 10.1038/ncb802 . 11575790 .
4. Monné M, Han L, Schwend T, Burendahl S, Jovine L . Crystal structure of the ZP-N domain of ZP3 reveals the core fold of animal egg coats . Nature . 456 . 7222 . 653–7 . 2008 . 19052627 . 10.1038/nature07599 . 2008Natur.456..653M . 4430083 . 11563/8930 . free .
5. Han L, Monné M, Okumura, H, Schwend, T, Cherry, AL, Flot, D, Matsuda, T, Jovine, L . Insights into egg coat assembly and egg-sperm interaction from the X-ray structure of full-length ZP3 . Cell . 143 . 3 . 404–15 . 2010 . 20970175 . 10.1016/j.cell.2010.09.041 . 18583237 . free . 11563/8931 . free .
6. Lin SJ, Hu Y, Zhu J, Woodruff TK, Jardetzky TS . Structure of betaglycan zona pellucida (ZP)-C domain provides insights into ZP-mediated protein polymerization and TGF-beta binding . Proc Natl Acad Sci U S A . 108 . 13 . 5232–6 . 2011 . 21402931 . 10.1073/pnas.1010689108 . 3069177. 2011PNAS..108.5232L . free .
7. Diestel U, Resch M, Meinhardt K, Weiler S, Hellmann TV, Mueller TD, Nickel J, Eichler J, Muller YA . Identification of a Novel TGF-β-Binding Site in the Zona Pellucida C-terminal (ZP-C) Domain of TGF-β-Receptor-3 (TGFR-3) . PLOS ONE . 8 . 6 . e67214 . 2013 . 23826237 . 10.1371/journal.pone.0067214 . 3695229. 2013PLoSO...867214D . free .
8. Bokhove M, Nishimura K, Brunati M, Han L, de Sanctis D, Rampoldi L, Jovine L . A structured interdomain linker directs self-polymerization of human uromodulin . Proc. Natl. Acad. Sci. U.S.A. . 113 . 6 . 1552–1557 . 2016 . 26811476 . 10.1073/pnas.1519803113 . 4760807. 2016PNAS..113.1552B . free .
9. Bokhove M, Jovine L . Structure of Zona Pellucida Module Proteins . Curr. Top. Dev. Biol. . Current Topics in Developmental Biology . 130 . 413–442 . 2018 . 29853186 . 10.1016/bs.ctdb.2018.02.007 . 9780128098028 .
10. Saito T, Bokhove M, Croci R, Zamora-Caballero S, Han L, Letarte M, de Sanctis D, Jovine L . Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1 . Cell Reports . 19 . 9 . 1917–1928 . 2017 . 28564608 . 10.1016/j.celrep.2017.05.011 . 5464963.
11. Jovine L, Qi H, Williams Z, Litscher ES, Wassarman PM . A duplicated motif controls assembly of zona pellucida domain proteins . Proc. Natl. Acad. Sci. U.S.A. . 101 . 16 . 5922–7 . 2004 . 15079052 . 10.1073/pnas.0401600101 . 395899 . 2004PNAS..101.5922J . free .
12. Stsiapanava A, Xu C, Brunati M, Zamora-Caballero S, Schaeffer C, Bokhove M, Han L, Hebert H, Carroni M, Yasumasu S, Rampoldi L, Wu B, Jovine L . Cryo-EM structure of native human uromodulin, a zona pellucida module polymer . EMBO J. . e106807 . 2020 . 39 . 24 . 33196145 . 7737619 . 10.15252/embj.2020106807 . free .
13. Stsiapanava A, Xu C, Nishio S, Han L, Yamakawa N, Carroni M, Tunyasuvunakool K, Jumper J, de Sanctis D, Wu B, Jovine L . Structure of the decoy module of human glycoprotein 2 and uromodulin and its interaction with bacterial adhesin FimH . Nat. Struct. Mol. Biol. . 29 . 3 . 190–193 . 2022 . 35273390 . 10.1038/s41594-022-00729-3 . 8930769 . free .
14. Callebaut I, Mornon JP, Monget P . Isolated ZP-N domains constitute the N-terminal extensions of Zona Pellucida proteins. . Bioinformatics . 23 . 1871–1874 . 17510169 . 10.1093/bioinformatics/btm265 . 2007. 15 . free .
15. Raj I, Sadat Al Hosseini H, Dioguardi E, Nishimura K, Han L, Villa A, de Sanctis D, Jovine L . Structural Basis of Egg Coat-Sperm Recognition at Fertilization . Cell . 169 . 7 . 1315–1326 . 2017 . 28622512 . 10.1016/j.cell.2017.05.033 . 5480393.