Desmoglein-2 F833C Is Predicted to Disrupt Hydrophobic Interactions With the Armadillo Repeat Region 1 of Plakoglobin

Desmoglein-2 (DSG2) is a desmosomal cadherin involved in cell-cell adhesion within cardiac tissue. A variant of uncertain significance (VUS), involving a phenylalanine-to-cysteine substitution at residue 833 (F833C), was identified and analyzed for its potential impact on the interaction between DSG2 and its intracellular binding partner plakoglobin. Molecular dynamics (MD) simulations, in silico pathogenicity predictions, and structural stability analyses were performed to assess the effects of this substitution. The F833C variant shows significantly reduced binding energy between DSG2 and plakoglobin, along with increased local structural flexibility measured by root mean square fluctuation (RMSF) at the mutation site and surrounding interaction interface. Notably, these local effects were observed despite apparent preservation of the overall global structure of the complex, which may indicate that the pathogenic effect of F833C predominantly involves local destabilization of the binding interface rather than gross conformational change. Structural analysis predicted that the phenylalanine-to-cysteine substitution disrupts hydrophobic interactions between DSG2 and plakoglobin's armadillo repeat region 1, potentially weakening desmosomal stability. Collectively, these findings suggest that the F833C variant may impair DSG2-plakoglobin interactions, supporting its potential contribution to arrhythmogenic right ventricular cardiomyopathy and warranting further experimental investigation.