Abstract:

Membrane proteins play a vital role in cell-cell signalling at the plasma membrane, requiring precise control of their activity, abundance, and localization. One powerful and irreversible way to regulate these proteins is through intramembrane proteolysis, a post-translational mechanism that, when disrupted, contributes to neurodegenerative diseases like Alzheimer’s and Parkinson’s (via dysfunction in intramembrane proteases such as gamma-secretase and PARL, respectively). Among this type of protease, secretase rhomboids stand out as highly expressed in neurons and essential for life, yet their specific roles in neuronal function remain a mystery. In this seminar, Adam will reveal how his lab is unravelling this mystery using a multidisciplinary approach, including AlphaFold modelling and molecular dynamics to explore structure-function relationships, screens to identify which proteins they cleave, and super-resolution microscopy to examine rhomboid localization and lateral diffusion at synapses

Bio:

My interest in protein signalling at membranes was fostered by my doctoral studies with Prof Tim Levine (UCL, UK), where I studied phosphoinositide signalling. My interest in regulation of membrane proteins by proteases was catalysed by my postdoc with Prof Catherine Rabouille (Hubrecht Institute, NL). Since then, my major research focus has been the control of cell signalling and behaviour via proteolysis at membranes. I moved to Prof Matthew Freeman’s lab (University of Oxford, UK) as a Marie Sklodowska-Curie fellow. There I discovered unexpected roles for the pseudoprotease iRhom2 in the regulation of the metalloprotease TACE/ADAM17, which triggers the release of the inflammatory cytokine, TNF, and many EGFR ligands. I also designed a screen to identify substrates of the rhomboid intramembrane protease, RHBDL2. A major discovery was that polytopic proteins, e.g. ion channels/transporters, may be common targets for intramembrane proteases, and that intramembrane proteases can recognise specific conformational states in these substrates. The approaches that I have developed have paved the way for discovery of intramembrane protease substrates more generally, which I aim to capitalise upon during my Sir Henry Dale Fellowship at the School of Biochemistry, University of Bristol. Many of these proteases are enriched in neurons, so I am taking advantage of the strong neuroscience research carried out here in Bristol.