STRUCTURE OF A FUNGAL HEME-IRON ACQUISITION PATHWAY

Iron acquisition from host tissues is a major virulence factor and a particular challenge to the pathogenic microorganism due to the high-affinity iron-chelation mechanism developed by the host that limit its bioavailability and providing the host nutritional immunity. Like many microbial pathogens, Candida albicans, a human commensal microorganism that can cause life-threatening systemic infections in immunocompromised individuals, has therefore evolved a mechanism for extracting iron from hemoglobin, the largest iron reservoir in the host. This pathway includes a relay network of secreted and GPI-anchored extracellular proteins containing a CFEM domain, that can extract heme from hemoglobin outside the cell and transfer the heme across the cell envelope from one CFEM protein to the next until delivered to the endocytic pathway. The crystal structure of the CFEM domain reveals a novel helical-basket fold consisting of six α-helices, stabilized by four disulfide bonds between eight conserved cysteine residues and a flexible N-terminal loop. The planar heme molecule is bound via a flat hydrophobic platform located on top of the helical basket and a unique aspartic acid residue serves as the axial ligand and makes the heme-iron coordination redox-sensitive. At the plasma membrane, the heme is endocytosed via the ESCRT pathway. To identify the transmembrane heme receptor that mediates the connection between the extracellular CFEM cascade and the endocytic steps, we used phylogenetic profiling. This revealed a new class of plasma membrane proteins, related to ferric reductases, that are essential for heme uptake. The molecular details of this fungal heme-iron acquisition pathway distinguish it from bacterial heme acquisition systems, indicating that fungi have evolved a novel solution to overcome iron scarcity.