Desmoplakin CSM models unravel mechanisms regulating the binding to intermediate filaments and putative therapeutics for cardiocutaneous diseases.
Arginine methylation
Arrhythmogenic cardiomyopathy
Desmin intermediate filaments
Desmoplakin carboxyterminal tail
Serine phosphorylation
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
05 Oct 2024
05 Oct 2024
Historique:
received:
21
05
2024
accepted:
19
09
2024
medline:
6
10
2024
pubmed:
6
10
2024
entrez:
5
10
2024
Statut:
epublish
Résumé
Arrhythmogenic cardiomyopathy (AC) is a common cause of sudden cardiac arrest and death in young adults. It can be induced by different types of mutations throughout the desmoplakin gene including the R2834H mutation in the extreme carboxyterminus tail of desmoplakin (DP CT) which remains structurally uncharacterized and poorly understood. Here, we have created 3D models of DP CT which show the structural effects of AC-inducing mutations as well as the implications of post-translational modifications (PTMs). Our results suggest that, in absence of PTMs, positively charged wildtype DP CT likely folds back onto negatively-charged plectin repeat 14 of nearby plakin repeat domain C (PRD C) contributing to the recruitment of intermediate filaments (IFs). When phosphorylated and methylated, negatively-charged wildtype DP CT would then fold back onto positively-charged plectin repeat 17 of PRD C, promoting the repulsion of intermediate filaments. However, by preventing PTMs, the R2834H mutation would lead to the formation of a cytoplasmic mutant desmoplakin with a constitutively positive DP CT tail that would be aberrantly recruited by cytoplasmic IFs instead of desmosomes, potentially weakening cell-cell contacts and promoting AC. Virtual screening of FDA-approved drug libraries identified several promising drug candidates for the treatment of cardiocutaneous diseases through drug repurposing.
Identifiants
pubmed: 39369039
doi: 10.1038/s41598-024-73705-0
pii: 10.1038/s41598-024-73705-0
doi:
Substances chimiques
Desmoplakins
0
DSP protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
23206Informations de copyright
© 2024. The Author(s).
Références
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