Structural Bases of ACTG2-dependent smooth muscle Myopathies

Visceral Myopathy is a rare hereditary disease in which patients’ intestine fails to contract, with debilitating, at times, fatal consequences. No drug exists for this disease and patients can only rely on palliative treatments which do not address the underlying mechanism. In most patients, the disease is caused by a defect in the gene for the enteric actin named ACTG2. Actins are among the most abundant proteins, they can be imagined as tiny lego bricks piling up to form long filaments, the skeleton of the cells. They are also essential for muscle contraction. We plan to use computational tools and experimental techniques able to visualize ACTG2 at an atomic level of detail. Exploiting these approaches we will answer questions such as: is the mutation changing the structure of ACTG2 bricks? In such a case, the bricks may not stick on each other anymore or the stacking process could be extremely slow? Another possibility is that the bricks may efficiently pile but fail to form a straight and steady filament. The answers to these questions may lead to develop an effective pharmacological therapy, which we will start exploring by the above-mentioned molecular and structural methodologies.