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

TL;DR

This study uses molecular dynamics simulations to reveal how post-translational modifications in desmoplakin's C-terminal tail regulate its conformational dynamics, affecting its interactions with intermediate filaments and its role in cell adhesion.

Contribution

It uncovers the structural mechanisms by which PTMs modulate desmoplakin's conformational states and interactions, providing insights into desmosome assembly and stability.

Findings

Phosphorylation of S2849 induces an 'arginine claw' in DPCTT.

Methylation of R2834 favors conformations for GSK3 phosphorylation.

DPCTT's conformational fluctuations suggest a competitive binding mechanism.

Abstract

Multicellular organisms consist of cells that interact via elaborate adhesion complexes. Desmosomes are membrane-associated adhesion complexes that mechanically tether the cytoskeletal intermediate filaments (IFs) between two adjacent cells, creating a network of tough connections in tissues such as skin and heart. Desmoplakin (DP) is the key desmosomal protein that binds IFs, and the DP-IF association poses a quandary: desmoplakin must stably and tightly bind IFs to maintain the structural integrity of the desmosome. Yet, newly synthesized DP must traffick along the cytoskeleton to the site of nascent desmosome assembly without 'sticking' to the IF network, implying weak or transient DP--IF contacts. Recent work reveals that these contacts are modulated by post-translational modifications (PTMs) in DP's C-terminal tail. Using molecular dynamics simulations, we have elucidated the structural basis of these PTM-induced effects. Our simulations, nearing 2 microseconds in aggregate, indicate that phosphorylation of S2849 induces an 'arginine claw' in desmoplakin's C-terminal tail (DPCTT). If a key arginine, R2834, is methylated, the DPCTT preferentially samples conformations that are geometrically well-suited as substrates for processive phosphorylation by the cognate kinase GSK3. We suggest that DPCTT is a molecular switch that modulates, via its conformational dynamics, DP's efficacy as a substrate for GSK3. Finally, we show that the fluctuating DPCTT can contact other parts of DP, suggesting a competitive binding mechanism for the modulation of DP--IF interactions.