There is interest in the development of drugs to treat
fungal infections due to the increasing threat of drug resistance, and here, we report the first crystallographic structure of the catalytic domain of a fungal
squalene synthase (SQS), Aspergillus flavus SQS (AfSQS), a potential
drug target, together with a bioinformatics study of fungal, human, and protozoal SQSs. Our X-ray results show strong structural similarities between the catalytic domains in these
proteins, but, remarkably, using bioinformatics, we find that there is also a large, highly polar helix in the
fungal proteins that connects the catalytic and membrane-anchoring transmembrane domains. This polar helix is absent in
squalene synthases from all other lifeforms. We show that the transmembrane domain in AfSQS and in other SQSs,
stannin, and
steryl sulfatase, have very similar properties (% polar residues, hydrophobicity, and hydrophobic moment) to those found in the "penultimate" C-terminal helical domain in
squalene epoxidase, while the final C-terminal domain in
squalene epoxidase is more polar and may be monotopic. We also propose structural models for full-length AfSQS based on the bioinformatics results as well as a deep learning program that indicate that the C-terminus region may also be membrane surface-associated. Taken together, our results are of general interest given the unique nature of the polar helical domain in fungi that may be involved in
protein-
protein interactions as well as being a future target for antifungals.