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Missense Mutations in Desmoplakin Plakin Repeat Domains Have Dramatic Effects on Domain Structure and Function.

Fiyaz Mohammed1, Elena Odintsova2, Martyn Chidgey2

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Disease-linked mutations in plakin repeat domains (PRDs) disrupt desmoplakin

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Area of Science:

  • Molecular and Cellular Biology
  • Structural Biology
  • Genetics and Disease

Background:

  • Plakin repeat domains (PRDs) are crucial for plakin protein interaction with intermediate filament (IF) cytoskeletons.
  • These interactions are essential for tissue integrity in cardiac and epithelial cells.
  • Mutations in PRDs are linked to cardiomyopathies and skin blistering diseases.

Purpose of the Study:

  • To investigate the functional and structural impact of 12 disease-associated missense mutations on desmoplakin's PRDs.
  • To elucidate the molecular mechanisms by which these mutations cause disease.

Main Methods:

  • Expression of mutant PRD proteins in bacterial cells to assess solubility.
  • Transfection of HeLa cells to evaluate the effect of mutations on protein localization to vimentin IFs.
  • Bioinformatic and structural modeling to predict the impact of mutations on PRD stability and function.

Main Results:

  • Five mutations (G2056R, E2193K, G2338R, G2375R, G2647D) resulted in insoluble PRD proteins.
  • The G2375R mutation impaired the targeting of desmoplakin to vimentin IFs in HeLa cells.
  • Deletion of PRD-B and PRD-C also compromised vimentin targeting, indicating their importance.
  • Modeling suggested mechanisms by which mutations destabilize PRDs and disrupt cytoskeletal linkages.

Conclusions:

  • Disease-causing mutations in desmoplakin PRDs can lead to protein insolubility and mislocalization.
  • These disruptions compromise essential interactions with the intermediate filament cytoskeleton.
  • Understanding these molecular mechanisms may inform therapeutic strategies for related cardiomyopathies and skin disorders.