New methods to capture protein dynamics of the TSC-mTOR signalling axis.

Tuberous sclerosis, or “tuberous sclerosis complex” (TSC), is a lifelong genetic disorder that affects millions of individuals. TSC is manifest in several organs, particularly the brain. Cases can be spontaneous, resulting from genetic mutations in the genes TSC1 or TSC2, however it can also be inherited. Disruption or mutations in the TSC genes can cause tumors or abnormal growths. However, the disease is characterized by various symptoms and severity, including seizures, neurological issues, multi-organ tumors, and behavioral problems. Individuals typically present symptoms from birth or in childhood with varied prognoses. TSC is considered a life-threatening disease, however with management individuals may live productive lives. There is currently no cure for TSC. This proposal will use cutting-edge cryo-electron microscopy and pioneer new biotechnologies to directly visualize and measure the molecules that are involved in TSC. Like machines, these molecules have precise components and mechanisms that govern their operation. These experiments will allow scientists to directly see these machines in action. Without a clear picture of what these molecules look like, we cannot understand their function. The research will take place within the wider Ellisdon laboratory (https://www.monash.edu/discovery-institute/ellisdon-lab). Our team collectively has expertise in membrane proteins, multi-component complexes, and integrative analytical methodologies. In addition to robust training in biochemistry and protein biology, the candidate will have opportunities to master modern methods in the life sciences such as, cryo-electron microscopy (1-5), cryo-electron tomography (4), X-ray crystallography (3), cross linking mass spectrometry (2,3), software development (python, machine learning), and biophysical methods (5). (1) Bayly-Jones et al., Nature Communications, 2019 (2) Lupton et al., Nature Structural & Molecular Biology, 2021 (3) Chang et al., Nature Structural & Molecular Biology, 2022 (4) Bayly-Jones et al., Nature Communications, 2022 (5) Bayly-Jones et al., Communications Biology, 2023