Substrates, Effectors and Inhibitors as Mechanistic Tools for Rhomboid Proteases

Rhomboids are a superfamily of evolutionary widespread polytopic membrane proteins. Despite their relatively recent discovery, rhomboids and other intramembrane proteases are already known to control a wide range of biologically and medically important processes. However, the number of cases in which there is knowledge of their function is tiny compared to the total number of intramembrane proteases known to exist. The relatively few that have been characterized regulate processes as diverse as EGF receptor signaling, mitochondrial dynamics, regulation of apoptotic stimuli, and apicomplexan parasite invasion.

The current research is expected to provide tools that may shed new light on this important and yet hardly studied family of membrane-associated enzymes, the rhomboids. Studying the interaction of the enzyme with the transition state analog inhibitors, along with the structure and function of the exosite, will provide data about the way these enzymes bind their target proteins within the membrane environment and about their catalytic mechanism, which is distinct from that of soluble serine proteases.