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Structural studies of human tafazzin

Structural studies of human tafazzin
Eric Ortlund, PhD, Associate Professor, Emory University, Atlanta, GA

Award - US $50,000 over 1-year period


Barth syndrome (BTHS) is a genetic disease driven by defects in the TAZ gene encoding the enzyme tafazzin, which is responsible for remodeling lipids, namely cardiolipins, essential for healthy mitochondria. Without functional tafazzin, mitochondrial membranes become unstable leading to their degradation and eventual cell death. This causes debilitating symptoms such as neuropathy, growth delays, skeletal and cardiomyopathy and premature death. Currently, there is no 3-dimensional structure for any tafazzin, which limits our ability to study molecular mechanisms that underlie this disease. Our proposed work aims to address this need by solving the X-ray structure of human tafazzin (hTAZ) in several functional states. We will link protein structure and conformational dynamics with its activity and provide a molecular framework with which to interpret the impact of clinical mutations. It is our hope that the ability to predict the impact and severity of TAZ mutations, will allow more personalized therapies to manage this disease. Our work will also generate reagents to allow us to specifically test and characterize BTHS causing mutations in hopes of elucidating possible therapeutic strategies to restore enzyme folding and/ or catalytic activity akin to what is being developed for cystic fibrosis.

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