Calpain Regulation and Dysregulation—Its Effects on the Intercalated Disk

Yöder, Mervin C.; Wright, Nathan T.; Borzok, Maegen A.

doi:10.3390/ijms241411726

Cited by 1 publication

(3 citation statements)

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“…Trypsin and chymotrypsin are not expressed in myocardia. Of the proteases that are expressed in the heart, matrix metalloproteins (MMPs), caspases, cathepsins, and calpains have been broadly implicated in heart diseases [12,37,38]. sDSP does not contain the target sequence for any caspase [39].…”

Section: Discussionmentioning

confidence: 99%

“…The desmosome is a proteinaceous structure spanning the cell membrane that links the intermediate filament network of one cell to its neighbor [3,10,11]. In the heart, the desmosome is part of the intercalated disk, which also contains adherens junctions and gap junctions [4,[11][12][13]. While these three intercellular connections have distinct roles, there is significant interplay between their function and regulation [12,14,15].…”

Section: Introductionmentioning

confidence: 99%

“…In the heart, the desmosome is part of the intercalated disk, which also contains adherens junctions and gap junctions [4,[11][12][13]. While these three intercellular connections have distinct roles, there is significant interplay between their function and regulation [12,14,15]. For instance, while a weakened desmosome most directly affects how cells relay and disperse physical force through the disruption of load-bearing intermediate filament networks, desmosomal mutations also alter electrical conduction and hamper signal transduction due to a secondary disruption of gap junction localization [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Prevention of Protease-Induced Degradation of Desmoplakin via Small Molecule Binding

Romov,

Nowzari,

Page

et al. 2024

JPM

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Desmoplakin (DSP) is a large (~260 kDa) protein found in the desmosome, the subcellular structure that links the intermediate filament network of one cell to its neighbor. A mutation “hot-spot” within the NH2-terminal of the DSP protein (residues 299–515) is associated with arrhythmogenic cardiomyopathy. In a subset of DSP variants, disease is linked to calpain hypersensitivity. Previous studies show that calpain hypersensitivity can be corrected in vitro through the addition of a bulky residue neighboring the cleavage site, suggesting that physically blocking calpain accessibility is a viable strategy to restore DSP levels. Here, we aim to find drug-like molecules that also block calpain-dependent degradation of DSP. To do this, we screened ~2500 small molecules to identify compounds that specifically rescue DSP protein levels in the presence of proteases. We find that several molecules, including sodium dodecyl sulfate, palmitoylethanolamide, GW0742, salirasib, eprosarten mesylate, and GSK1838705A prevent wildtype and disease-variant-carrying DSP protein degradation in the presence of both trypsin and calpain without altering protease function. Computational screenings did not predict which molecules would protect DSP, likely due to a lack of specific DSP–drug interactions. Molecular dynamic simulations of DSP–drug complexes suggest that some long hydrophobic molecules can bind in a shallow hydrophobic groove that runs alongside the protease cleavage site. Identification of these compounds lays the groundwork for pharmacological treatment for individuals harboring these hypersensitive DSP variants.

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