Desmoplakin CSM models unravel mechanisms regulating the binding to intermediate filaments and putative therapeutics for cardiocutaneous diseases

Area of Science:

• Cardiovascular Biology
• Molecular Genetics
• Structural Biology

Background:

• Arrhythmogenic cardiomyopathy (AC) is a primary cause of sudden cardiac death in young adults.
• Mutations in the desmoplakin gene are implicated in AC pathogenesis.
• The carboxyterminus tail of desmoplakin (DP CT) and the R2834H mutation's structural role are poorly understood.

Purpose of the Study:

• To elucidate the structural mechanisms underlying AC development caused by desmoplakin mutations.
• To investigate the impact of post-translational modifications (PTMs) on desmoplakin C-terminus structure and function.
• To identify potential therapeutic strategies for AC through drug repurposing.

Main Methods:

• Development of 3D structural models of the desmoplakin C-terminus (DP CT).
• In silico analysis of wildtype and R2834H mutant DP CT structures.
• Virtual screening of FDA-approved drug libraries.

Main Results:

• Wildtype DP CT structure is influenced by PTMs, affecting intermediate filament (IF) recruitment.
• The R2834H mutation prevents PTMs, leading to a constitutively positive DP CT tail.
• Mutant desmoplakin may aberrantly interact with cytoplasmic IFs, potentially weakening cell-cell adhesion and promoting AC.
• Several drug candidates for cardiocutaneous diseases were identified.

Conclusions:

• The R2834H mutation in desmoplakin disrupts normal DP CT function by preventing PTMs, leading to aberrant IF interactions and AC.
• Structural insights into DP CT provide a basis for understanding AC.
• Drug repurposing holds promise for treating AC and related cardiocutaneous diseases.