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Prof. Daniel Kornitzer

Room: 
MoSE 3201A
Date: 
Tuesday, September 3, 2019 - 11:00am to 12:00pm

"From phylogenetics to crystal structure in the elucidation of a novel microbial heme-iron utilisation pathway”

 

To overcome iron-withholding defenses deployed by the host, many microbial pathogens have evolved mechanisms for extracting iron from hemoglobin, the largest iron store in the host. In the fungal pathogen Candida albicans, we identified a heme-iron utilization pathway that includes an extracellular cascade of small secreted and GPI-anchored proteins containing a CFEM domain, defined by an 8-cysteine sequence signature. These proteins all are able to capture heme from hemoglobin and to exchange heme among themselves, consistent with a pathway in which heme is extracted from hemoglobin outside the cell and is then transferred from one CFEM protein to the next across the cell wall, until it reaches the plasma membrane. We solved the structure of the secreted hemophore Csa2, and found that its CFEM domain adopts a novel protein fold, held together by 4 disulfide bonds generated by the 8 conserved cysteines. The heme is bound between a flat hydrophobic platform located on top of the CFEM domain and a flexible N-terminal extension, consistent with rapid ligand binding and release. An exceptional Asp heme-iron coordination confers redox sensitivity to the interaction. At the plasma membrane, the heme is endocytosed by a mechanism involving the ESCRT pathway. To identify the predicted transmembrane heme receptor that connects the extracellular CFEM network with the endocytic pathway, we turned to phylogenetic profiling: taking advantage of the hundreds of fungal genomes available, we screened for genes jointly present across fungi with the CFEM heme transfer cascade genes. This enabled us to identify a new class of plasma membrane proteins that are essential for heme uptake. The hemoglobin-iron utilization pathway that emerges from these studies, which is distinct from bacterial systems, indicates that fungi have evolved a unique solution to the heme-iron acquisition problem. The presence of homologous CFEM hemophore cascade genes in many environmental fungi suggests that the ubiquitous heme molecule constitutes a common iron source for microorganisms.

Contact Information: 
Host:  Prof. Amit Reddi
Map of Georgia Tech

School of Chemistry & Biochemistry

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