Structural insights into mechanisms of zinc scavenging by the Candida albicans zincophore Pra1

Candida albicans causes over 400,000 life-threatening, and an additional half a billion of mucosal infections annually. In response to infection, the host limits essential micronutrient availability, including zinc, to restrict growth of the invading pathogen. As assimilation of zinc is essential for C. albicans pathogenicity, limitation induces secretion of the zincophore protein Pra1 to scavenge zinc from the host. Pra1 also plays a number of important roles in host-pathogen interactions and is conserved in most fungi. However, the structure of fungal zincophores is unknown. Here, we present cryo-EM structures of C. albicans Pra1 in apo- and zinc-bound states, at 2.8 and 2.5 Å resolution respectively. Our work reveals a hexameric ring with multiple zinc binding sites. Through genetic studies, we show that these sites are essential for C. albicans growth under zinc restriction but do not affect the inflammatory properties of Pra1. These data create a foundation for future work to explore the structural basis of Pra1-mediated host-pathogen interactions, C. albicans zinc uptake, as well as therapeutics development.