Grant: Operating Grant

The membrane bilayer provides a partition between intracellular and extracellular compartments of organelles and cells. Membrane proteases have evolved to allow transfer of information across this partition. Rhomboid intramembrane proteases (named for a Drosophila mutant phenotype) are enzymes located within the lipid bilayer of cells. By cleaving the peptide bond of another membrane protein, they release soluble factors that can act in signalling events. They are novel in that the enzyme carries out its function in the lipid environment as opposed to the intracellular compartments with traditional well-characterized soluble proteases. Rhomboid proteases are found in all living organisms. They play diverse roles in signalling. In bacterial systems, they assist in regulating cell populations and therefore are important regulators of infection. Rhomboids play a role in human malaria by facilitating parasite invasion. In human cells, rhomboid assists in preventing cell death. Defects in rhomboid proteases are associated with autosomal dominant hereditary blindness, Type II diabetes, and epithelial cancers such as those associated with the breast, head and neck. Using structural techniques such as X-ray crystallography, cryo-electron microscopy, solution small angle scattering along with traditional biochemistry, we aim to uncover the important details of this novel protease family with diverse yet significant functions in human disease.