  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.
