Addition of a secondary single point mutation (L518Y) partially blocks access to the calpain target site in DSP clinical variants, resulting in restored DSP protein levels.
Introducing an L518Y mutation acts as a 'molecular band-aid' to stabilize calpain-sensitive DSP variants, offering a potential novel strategy for treating DSP-related cardiomyopathies.
-terminal third of the DSP protein (specifically, residues 299-515) is associated with both cardiomyopathies and skin defects. In select DSP variants, disease is linked specifically to the uncovering of a previously-occluded calpain target site (residues 447-451). Here, we partially stabilize these calpain-sensitive DSP clinical variants through the addition of a secondary single point mutation-tyrosine for leucine at amino acid position 518 (L518Y). Molecular dynamic (MD) simulations and enzymatic assays reveal that this stabilizing mutation partially blocks access to the calpain target site, resulting in restored DSP protein levels. This 'molecular band-aid' provides a novel way to maintain DSP protein levels, which may lead to new strategies for treating this subset of DSP-related disorders.
Hoover et al. (Wed,) conducted a other in DSP-related disorders (cardiomyopathies and skin defects). Secondary single point mutation L518Y in DSP was evaluated on DSP protein levels and access to calpain target site. Addition of a secondary single point mutation (L518Y) partially blocks access to the calpain target site in DSP clinical variants, resulting in restored DSP protein levels.