Female Fertility And The Zona Pellucida - ELife

The mouse ZP is constructed of three glycosylated proteins, called mZP1–3, that are encoded by single-copy genes located on different chromosomes (Liang and Dean, 1992; Wassarman and Litscher, 2018). mZP2 and mZP3 are monomers and mZP1 is a dimer of identical polypeptides connected by an intermolecular disulfide. The human ZP is constructed of four glycosylated proteins, called hZP1–4, that are also encoded by single-copy genes located on different chromosomes (Gupta, 2018). hZP2 and hZP3 are monomers, hZP1 is a dimer of identical polypeptides connected by an intermolecular disulfide, and hZP4 is either a monomer or dimer held together by noncovalent interactions. Mouse and human ZP protein sequences are ≃63% identical and ≃84% similar and this suggests that the proteins perform identical functions (Chothia et al., 2003). In this context, it has been found that human ZP proteins can substitute for mouse ZP proteins in the mouse ZP (Rankin et al., 2003). In mouse oocytes mZP2 and mZP3 form heterodimers in the extracellular space which then polymerize into long fibrils that exhibit a structural repeat (≃15 nm) (Greve and Wassarman, 1985; Wassarman and Mortillo, 1991). The fibrils are crosslinked by mZP1 and possibly by many noncovalent interactions between fibrils. It can be assumed that ZP fibrils surrounding human oocytes are constructed in a similar manner during oogenesis.

ZP proteins are synthesized as polypeptide precursors by growing oocytes and are processed by proteases prior to secretion into the extracellular space. Nascent mouse and human ZP polypeptides have many features in common (Figure 4). Among these features are: (1) A short signal sequence at the amino- terminus that targets nascent ZP proteins to the secretory pathway and is removed prior to secretion; (2) A ZP domain (ZPD) that consists of two subdomains, ZP-N and ZP-C, separated by a short linker region. The subdomains adopt immunoglobulin-like folds, a three-dimensional structure thought to have arisen ≃750 million years ago in sponges for use in vertebrate extracellular recognition systems (Barclay, 2003). The ZPD is essential for polymerization of extracellular proteins into fibrils and has been found in hundreds of proteins in a wide variety of organisms, from jellyfish to humans (Jovine et al., 2002; Jovine et al., 2005; Plaza et al., 2010; Litscher and Wassarman, 2015); (3) Internal and external hydrophobic patches (IHP and EHP, respectively) that interact with each other in ZP polypeptide precursors and prevent formation of fibrils in oocytes prior to proteolytic processing and secretion; (4) A carboxy-terminal propeptide (CTP) that contains a hydrophobic transmembrane domain used to insert nascent ZP proteins into secretory granule and plasma membrane and a short hydrophilic cytoplasmic tail that is removed by proteolytic cleavage at the consensus furin cleavage site (CFCS) during secretion; (5) mZP1, hZP1, and hZP4 also contain a trefoil domain (TD), possibly involved in crosslinking of ZP fibrils (Järvå et al., 2020), and one extra copy of subdomain ZP-N (N1) near their amino-terminus; mZP2 and hZP2 have three extra copies of ZP-N (N1–3) near their amino-terminus (Callebaut et al., 2007). Processing, secretion, and polymerization of nascent ZP proteins are regulated by polypeptide sequence elements such as the ZP-N, ZP-C, CFCS, CTP, IHP, and EHP (Zhao et al., 2003; Jovine et al., 2004; Jimenez-Movilla and Dean, 2011; Bokhove and Jovine, 2018; Wassarman and Litscher, 2018).

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