Structural Basis of Tuberous Sclerosis Complex Assembly and Dysregulation in Disease
Abstract
The tuberous sclerosis complex (TSC) is a large assembly of three proteins that act as a master switch to turn off cell growth and proliferation. Genetic mutation in TSC genes can cause the TSC to either partially or completely lose this key regulatory function. This may result in aberrant cell growth that clinically manifests in the many debilitating symptoms of TSC disorder. The disorder is characterized by the formation of tumors in a range of organs and tissues including the brain, heart, kidneys, skin, and lungs. It effects over 2 million people worldwide and major inroads are being made into characterizing the cellular pathways that are dysregulated in the disease. However, how this assembly of TSC proteins acts as master switches at the molecular level has not been determined. This remains an important problem in TSC research that limits our understanding of the normal function of the complex and how this activity changes in disease. This project will provide a snapshot of the TSC at the near-atomic level by using interdisciplinary and cutting-edge techniques including cryo-electron microscopy. Recent advancements in these fields have revolutionized our ability to capture images of proteins and effectively allow us to “zoom-in” on these proteins to take pictures at a clear enough resolution to describe how they function. This information can be used to examine how TSC regulates cell growth signals and to understand how this is dysregulated when the function of the TSC is reduced or absent in disease. As such, these experiments are closely aligned to the Tuberous Sclerosis Complex Research Program Focus Area of “Gaining a deeper knowledge of TSC signaling pathways and the cellular consequences of TSC deficiency.” This type of basic research has applicability to patient outcomes in multiple areas. A major flow-on effect to TSC research is expected from the structural insights proposed within this application. High-resolution images of the TSC will allow researchers to specifically probe key structural regions and cellular interaction sites for their role in TSC signaling and dysregulation. As evidenced by high citation rates, structural biology breakthroughs are often major drivers of both basic research science and therapeutic development. In the medium term, the data derived from this proposal will set a key foundation for understanding how genetic mutations in TSC genes result in disease. For example, why does a mutation in one location of TSC2 cause severe disease in patients while in other patients a mutation in a different TSC2 location results in minor symptoms? The project proposed here will allow us to begin to rationalize a large part of this effect. We will be able to visualize the location of mutations on our TSC images, enabling us to determine if they are in critical areas or if they are in regions of little functional importance. Upon further research, this “mapping” of mutations may allow us to make critical disease-specific decisions based upon the location of a patient’s TSC1/2 mutation(s). For example, at what age and how severe may the disease manifest and at what age should therapeutic treatment commence? Beyond the initial studies described in this proposal, the structures generated will form the foundation for future work in the field to identify and develop better therapeutic compounds to treat TSC. These therapeutics may target and attempt to rescue the loss-of-function of the TSC complex itself. Or, for example, may facilitate development of a drug to mimic the molecular actions of the TSC within the cell to effectively turn aberrant cell growth off. Ultimately, structural insights such as those proposed here have consistently driven the development of better therapeutics in a host of diseases. In the long term, we expect a similar scenario in the development of drugs to treat of TSC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910182
Entities
People
- Andrew M Ellisdon
Organizations
- Monash University
- United States Army