Conformational Surveillance of signalling proteins in the plasma membrane

The distinct activities of polytopic channels, transporters and receptors are essential for cell signalling in response to external stimuli, and their dysfunction is frequently associated with disease.

My research has revealed that these plasma membrane proteins undergo Conformational Surveillance by intramembrane proteases: their distinct conformations are recognised and subsequently downregulated by transmembrane domain cleavage.

Substrates have never been identified for many intramembrane proteases; I propose this is largely due to a previous lack of systematic screening approaches, and that proteins with more than one transmembrane domain have not been fully explored as substrates.

The overarching aim in this fellowship is to discover the mechanisms that underpin Conformational Surveillance, and to reveal its full repertoire of functions.

My four main goals are: 1) to explore newly identified examples of Conformational Surveillance; 2) to examine whether intramembrane proteases of different families share this molecular activity; 3) to understand the mechanistic coupling of intramembrane proteolysis and lysosomal degradation; 4) to investigate Conformational Surveillance in neurons, where many intramembrane proteases are highly expressed.

Overall, this research programme will shed light on a potentially widespread yet overlooked branch of cell surface proteostasis.