Our Research
The function of signalling receptors, transporters and channels in the plasma membrane is essential for all living cells. Their biological importance is highlighted by the observation that ~70% of clinical drugs target integral membrane proteins and that even subtle mutations or defects in their activity lead to human disease.
The major goal of our group is to define the molecular mechanisms for integral membrane protein regulation within the plasma membrane. We use neurons as a cellular model, as they have multiple specialised plasma membrane domains and a unique proteome comprising signalling receptors and channels. In particular, we focus on relatively unexplored regulators – such as intramembrane proteases – that have the ability to “read” and respond to the dynamics of transmembrane domains of these classes of protein.
We anticipate that our study of proteostasis and quality control of membrane proteins will shed light on the molecular basis of neurodegenerative disorders and cancer.
Proteostasis at the neuronal cell surface
Neurons – such as the hippocampal neuron that is pictured (taken by Anna) – are terminally differentiated, post-mitotic and long-lived, which poses a unique proteostatic challenge. Integral membrane proteins at the surface of neurons are critical for a wide variety of neuronal functions. We investigate the mechanisms that underlie their turnover at the cell surface of neurons, which relate to processes such as learning and memory and can go awry in disease.
Conformational Surveillance
Cell surface receptors, transporters and channels all undergo large conformational changes that drive their activity. We have found that certain proteins can recognise these dynamics within the bilayer – and act to downregulate them. We will further investigate identified examples of this process – and aim to discover further intrabilayer regulators of membrane protein activity and abundance.
Intramembrane proteolysis
Intramembrane proteases exist in all kingdoms of life, yet we have a limited understanding of what they do in mammals. We have developed new ways to identify and screen for their substrates, which is a critical step in elucidating their function. We focus our efforts on plasma membrane resident RHBDL1, RHBDL2 (subcellular localisation pictured), RHBDL3 and SPPL2b.