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

Candida albicans causes more than 400,000 life-threatening, and half a billion mucosal infections annually. In response to infection, the host limits availability of essential micronutrients, including zinc, to restrict growth of the invading pathogen. As assimilation of zinc is essential for C. albicans pathogenicity, its limitation induces the 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 not known. Here, we present the first cryogenic electron microscopy structures of C. albicans Pra1 in its apo- and zinc- bound states, at 2.8 and 2.5 [A] resolution respectively. Our work reveals a hexameric ring-like assembly with multiple zinc binding sites. Through genetic studies, we show that one of these zinc binding sites is essential for C. albicans growth under zinc restriction but does not affect the inflammatory properties of Pra1. These data provide a foundation for future work to explore the structural basis of Pra1-mediated host-pathogen interactions, C. albicans zinc uptake, as well therapeutics development.