Arrhythmogenic cardiomyopathy (ACM), a genetic disease characterized by infiltration of fibrofatty tissue into the myocardium, is typically diagnosed by sudden cardiac death and has no viable treatment. About 60% of ACM patients have variants in genes encoding proteins of the desmosome, a structure essential for cardiomyocyte coupling. Mutations in desmoplakin, a desmosomal protein, account for about 20% of variants causing ACM. Many of these variations occur in the N-terminal third of desmoplakin at a designated hotspot region. A target site for the protease calpain has been identified within the hotspot (aa 447-451). We have previously shown that select hotspot variants, including S299R and R451G, increase desmoplakin’s susceptibility to proteolysis by calpain. Herein, we performed molecular dynamics on wild-type desmoplakin and desmoplakin carrying the S299R or R451G variants. Snapshots of the proteins at 10-ns intervals were used to measure the exposed surface area of the calpain target site. We found a trend of more exposed surface area in the variants compared to wild-type protein. To mitigate this increased exposure, we introduced a large amino acid side chain to protect the area. Specifically, we substituted tyrosine for leucine at position 518 (L518Y). Surface area analysis was also performed on S299R, R451G, and wild-type desmoplakin with the L518Y mutation and a trend of decreasing exposed surface area was observed. However, the tyrosine side chain cannot protect the calpain target site 100% of the time, as it exists in both “flipped in” and “flipped out” positions. In its flipped in position, the tyrosine side chain covers the target site, reducing its exposed surface area and protecting desmoplakin from calpain cleavage. In its flipped out position, the side chain is angled away from the target site, leaving the area exposed. These results warrant data collection at closer time intervals to better study the protecting abilities of the L518Y mutation.

Molecular band-aid reduces area of desmoplakin exposed for cleavage by calpain

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.