Claws, Disorder, and Conformational Dynamics of the C Terminal Region of Human Desmoplakin

Cellular adhesion is governed by desmosomes, which are large inter-cellular junctions that act by tethering the intermediate filaments of separate cells. Intermediate filaments bind to a protein known as desmoplakin (DP), which in turn is linked to a membrane-bound cadherin complex. The serine-rich C-terminal region of DP was recently shown to modulate its binding to intermediate filaments. Several phosphorylation sites on the C-terminal region have been identified via mass spectrometry, and have been shown to regulate the binding strength. To elucidate the molecular mechanism of this coupling, and the role of specific post-translational modifications (PTM), we are using molecular dynamics simulations to examine the structural behavior of several forms of desmoplakin (wild-type, mutants, with and without PTMs). Our results indicate that the phosphorylation of residue S2849 leads to the formation of an arginine claw that is absent in the non-phosphorylated protein. This finding at least partly elucidates the phenotypes stemming from several disease-linked human mutations in DP. We are currently determining if R2834H, a mutation that has been linked to arrhythmogenic right ventricular cardiomyopathy, disrupts the claw structure; we are also examining the effects of methylation of R2834, which has recently been shown to control the extent of phosphorylation. This work will illuminate the structural mechanisms by which DP adhesion is ultimately controlled.