In an ingenious gain-of-function experiment, ZP2 was shown to be critical for human sperm-egg binding. Human sperm do not bind to the zona of mouse eggs, so Baibakov and colleagues (2012) added the different human zona proteins separately to the zona of mouse eggs. Only those mouse eggs with human ZP2 bound human sperm. Once bound to ZP2, the sperm can start lysing a channel into the zona. In the other pathway, sperm with intact acrosomes become bound to ZP3 (Bleil and Wassarman 1980, 1983). The binding to ZP3 causes the sperm to undergo the acrosome reaction on the zona. From here, the sperm binding is transferred to ZP2.
The sperm receptor that binds to the zona proteins has not yet been identified. It may be a complex containing several proteins that bind to both the protein and the carbohydrate portions of the zona glycoproteins (Chiu et al. 2014). As the sperm move toward the egg through the zona pellucida, contacts with the zona must be continually made, broken, and remade. The mechanism for this is not known, but two important proteins may be the acrosomal proteins acrosin and MMP2 (matrix metaloproteinase-2). MMP2 is a protein that digests extracellular matrices (such as the zona) and may be responsible for digesting a pathway to the oocyte. Acrosin may bind secondarily to the zona, keeping the sperm in the channel it creates (see Kerns et al. 2018).
Baibakov, B., N. A. Boggs, B. Yauger, G. Baibakov and J. Dean. 2012. Human sperm bind to the N-terminal domain of ZP2 in humanized zonae pellucidae in transgenic mice.J. Cell Biol.197: 897–905.
Bleil, J. D. and P. M. Wassarman. 1980. Mammalian sperm and egg interaction: Identification of a glycoprotein in mouse-egg zonae pellucidae possessing receptor activity for sperm.Cell20: 873–882.
Bleil, J. D. and P. M. Wassarman. 1983. Sperm-egg interactions in the mouse: sequence of events and induction of the acrosome reaction by a zona pellucida glycoprotein.Dev. Biol. 95: 317–324.
Chiu, P. C., K. K. Lam, R. C. Wong and W. S. Yeung. 2014. The identity of zona pellucida receptor on spermatozoa: an unresolved issue in developmental biology.Semin. Cell Dev. Biol. 30: 86–95.
Kerns, K., M. Zigo, E. Z. Drobnis, M. Sutovsky, and P. Sutovsky. 2018. Zinc ion flux during mammalian sperm capacitation. Nat. Commun. 9: 2061.
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