ZP2 (zona pellucida glycoprotein 2) is a critical structural and functional component of the zona pellucida, the extracellular matrix surrounding mammalian oocytes 1. As a major subunit of zona pellucida fibrils, ZP2 serves dual roles: it acts as a secondary sperm receptor and mediates sperm-egg recognition during fertilization 1. Acrosome-reacted sperm bind to ZP2 polypeptide via their inner-acrosomal membrane, enabling penetration of the zona pellucida 1. Following fertilization, ovastacin cleaves ZP2 near its amino-terminus, triggering oligomerization that extensively cross-links zona pellucida filaments, rigidifying the egg coat and preventing supernumerary sperm penetration—a key mechanism of the secondary polyspermy block 2. Mutations in ZP2 cause oocyte maturation arrest and female infertility; heterozygous missense mutations reduce ZP2 expression and impair secretion, while homozygous mutations lead to complete zona pellucida absence and oocyte degeneration 34. Notably, ZP2 has been co-opted in human-specific cerebellar synapse development, where it regulates synaptic protein levels and neuronal activity in granule cells 5. The amino-terminal region of ZP2 is particularly critical for sperm binding and has been exploited for sperm selection in assisted reproductive technologies 6.