The protein dysferlin initiates and controls the process of repairing damage to the cell membranes of muscles during physical movement. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding a team led by Professor Joe Baio from Oregon State University to investigate the key chemical interactions that dictate dysferlin repairs and manipulate biological membranes. Certain types of muscular dystrophy, including Limb-girdle muscular dystrophy type 2B and Miyoshi distal myopathy muscular dystrophy are connected to mutations within the dysferlin protein. This project specifically studies how the interactions of dysferlin with components of the cell membrane start the repair process. Results from this research help unlock answers to how chemical miscues lead to downstream musculoskeletal diseases. Professor Baio plans to integrate this project into an outreach program designed to increase the representation of Native Americans in STEM disciplines by providing training opportunities for both Native students and instructors from a local American Indian school.
The overall goal of this project is to establish the chemical principles that dictate how key proteins repair and manipulate biological membranes. When muscle sarcolemma is damaged, calcium leaks into the cell and exposure to calcium ions trigger a binding event between dysferlin's outer domain and an intracellular lipid vesicle. It has been postulated that following lipid binding, dysferlin then directs this liposome towards the damaged portion of the membrane, where it fuses and patches the damaged membrane. In this project, sum frequency vibrational spectroscopic approaches is applied to resolve the chemical interactions between dysferlin and phospholipids that trigger the initial lipid binding step and guide vesicle shuttling. This approach provides the geometry and positions of important atoms and protein structures at the dysferlin-plasma membrane interface. These approaches are then repeated for dysferlin variants associated with dysferlinopathies demonstrating how mutations within the protein contribute to a failure of this mechanism. Finally, this experimental work also provides crucial evidence that sum frequency vibrational spectroscopy-based approaches can potentially be applied to the dissection of any complex membrane protein-lipid interaction. In addition, Professor Baio works with teachers and students from a local Native American boarding school and provides them with opportunities to engage in research during the summers.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
