Leveraging integrative structural biology discoveries to unravel key molecular interactions in fertilization and antibacterial defense

By forming resilient supramolecular structures that expose branches with highly diversified binding properties, zona pellucida (ZP) module glycoproteins perform a wide range of biological functions from hydra to human.

Among this large family of molecules, my laboratory has been focusing on two archetypal systems: vertebrate egg coat proteins ZP1-4, which form heteromeric filaments that play key roles in fertilization, and human glycoprotein uromodulin (UMOD), whose homopolymers counteract urinary tract infection.

Our recent structure determination of both types of filaments revealed the molecular basis of ZP module-mediated protein polymerization, contributed to unveiling the mechanism of the egg coat block to polyspermy, and complemented parallel studies of how UMOD recognizes bacterial fimbrial adhesin FimH.

Building upon these findings, we now propose to reexamine the hypothesis that ZP3 O-glycans may mediate sperm binding to the egg coat, in light of the architecture of its filaments.

In parallel, we will visualize the structural changes that harden the egg coat to prevent polyspermy and protect the developing embryo, as well as investigate how proteases dismantle this supramolecular shield at hatching.

While these studies will have major implications for human reproductive medicine, parallel work on how UMOD filaments organize into velcro-like surfaces may bring a new perspective on their antibacterial activity and involvement in the pathogenesis of cast nephropathy.