C3 is delighted to share that a research grant has been awarded to Dr. Peter Davies of Queen’s University in Ontario, Canada. The project, titled “Solving the structure of Calpain 3 and assessing the impact of LGMD2A/R1,” aims to determine the three-dimensional structure of the Calpain 3 enzyme. Further, his lab will investigate how LGMD2A/R1-causing variants impact structure, including the interaction between Calpain 3 and the muscle protein titin. These studies can be used to guide the development of future drugs and genetic therapies.
A surprising discovery
Dr. Davies and colleagues recently expanded the field’s understanding of Calpain 3 with the unexpected discovery that it exists as a hexamer (a complex of six Calpain 3 molecules) until it interacts with a large muscle protein called titin. Upon binding to titin, the Calpain 3 hexamer switches to become a dimer (a complex of two molecules). It is thought that this switch regulates the activity of Calpain 3 within muscle. With the new C3 grant, this experienced team will use advanced electron microscopy techniques and biochemical approaches to further understand the structure of Calpain 3. They will test how the structure is affected by different LGMD2A/R1-causing variants (mutations that have been found in patients), as well as how these variants impact the interaction of Calpain 3 with titin.
Towards rational design
This project provides a novel approach to understanding how patient variants that lead to LGMD2A/R1 impact the structure and function of Calpain 3. Therefore, it has the potential to categorize different types of variants and to predict the impact of novel variants. In addition to improving diagnostic precision, the project also has the potential to support future studies using rational design to develop therapies.
“Calpain 3 has historically been an extremely difficult protein to study because it undergoes rapid self-destruction (autolysis) when isolated. Dr. Davies tackled this challenge by using a ‘dissect-and-build’ method to solve the structure of individual pieces, which led to the surprise that Calpain 3 can form a hexamer. We are excited to fund Dr. Davies’ team so they can explore the impact of patient variants on the structure which can improve diagnostics and may – in the future – allow for the design of targeted therapies.” Jennifer Levy, C3 Scientific Director
“We were delighted to see how the Calpain 3 multimer changed size when the titin fragment was present. This confirms some pioneering results from other labs about the Calpain 3 binding site in muscle and suggests we might find some LGMD2A/R1 mutations that cause the dystrophy by interfering with Calpain 3 binding.” Peter Davies, C3 Research Grant Recipient