NeuroRhomboid · Discovering the signalling pathways and physiology of active rhomboid proteases in the brain

Discovering the signalling pathways and physiology of active rhomboid proteases in the brain

Protease enzymes catalyse irreversible post-translational modifications that control many distinct cellular processes. An important class are intramembrane proteases, which have catalytic activity that is confined within the lipid bilayer. Intramembrane proteases function to cleave their specific transmembrane substrates. To our knowledge, the human genome encodes fourteen intramembrane proteases, of which five are rhomboid proteases. Rhomboid proteases are defined and characterised by their distinct mode of catalysis (a catalytic dyad of serine and histidine residues) and their evolutionarily conserved six-transmembrane domain core structure. Despite their intensive study, we do not know the physiological roles for mammalian rhomboid proteases; in particular few roles have been ascribed for the four rhomboids that are localised within the secretory pathway. This is mainly due to a lack of identified substrates. The core aim of this project is to identify novel substrates for rhomboid proteases, to enable us to expose their physiological and medical significance. Several intramembrane proteases have been linked to human pathologies such as neurodegeneration and cancer. Perhaps the most well known example is that of gamma-secretase and its pivotal role in the formation and accumulation of beta-amyloid, which characterises Alzheimer’s Disease. Interestingly, rhomboid proteases have also been linked to Alzheimer’s Disease; RHBDL4 has been shown to process APP but in a distinct manner to that of gamma-secretase. Furthermore, PARL, the mitochondrially targeted rhomboid protease, cleaves PINK1, a mitochondrial kinase mutated in Parkinson’s Disease. Overall, these examples illustrate the potential impact that can be made by the discovery of a protease-substrate relationship. Rhomboid proteases are present in all kingdoms of life. Such conservation throughout evolution suggests these enzymes have important functions in human biology, which are only now being illuminated, and can only be fully comprehended through substrate discovery. The overall objective of the action is to discover the physiological and medical significance of active rhomboid proteases in mammals. Two largely uncharacterised rhomboids are enriched in the brain, and are the main focus of our investigations. To achieve our objective, we work toward three goals: 1) to identify novel substrates for the rhomboid proteases, 2) to validate the identified substrates biologically and 3) to uncover their physiological significance through the screening of mutant cells and model organisms.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз