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How ARVC-Related Mutations Destabilize Desmoplakin: An MD Study

Csaba Daday1, Laura Marlene Mateyka2, Frauke Gräter1

  • 1Interdisciplinary Center for Scientific Computing, Heidelberg University, Mathematikon, Heidelberg, Germany; Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.

Biophysical Journal
|February 19, 2019
PubMed

Insights

Buried mutations in arrhythmogenic right ventricular cardiomyopathy (ARVC) destabilize desmoplakin, a key protein in heart cell junctions. This molecular instability impairs desmosome integrity under mechanical stress, explaining ARVC disease progression.

Area of Science:

  • Cardiovascular Biology
  • Molecular Biophysics
  • Genetics of Heart Disease

Background:

  • Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial heart condition.
  • Mutations in desmosomal proteins, particularly desmoplakin, are linked to ARVC.
  • The molecular mechanisms by which these mutations cause ARVC remain unclear.

Purpose of the Study:

  • To investigate the mechanical effects of ARVC-associated mutations in the desmoplakin plakin domain.
  • To understand how specific mutations alter protein dynamics and structural integrity.

Main Methods:

  • Utilized molecular dynamics simulations to analyze desmoplakin plakin domain dynamics.
  • Performed simulations to assess the impact of mutations on interdomain hinge flexibility.
  • Applied external forces to determine the rupture forces of mutated desmoplakin constructs.

Main Results:

  • Most surface-exposed mutations showed minimal impact on desmoplakin dynamics.
  • Buried mutations significantly increased the flexibility of the desmoplakin junction.
  • Buried mutations reduced the force required to rupture desmoplakin constructs.

Conclusions:

  • Buried ARVC mutations destabilize desmoplakin at a critical molecular interface.
  • This destabilization compromises desmosome integrity under mechanical tension.
  • Findings provide a molecular basis for ARVC pathogenesis linked to desmoplakin mutations.

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