jp6b03261_si_001.pdf (27.35 MB)
Claws, Disorder, and Conformational Dynamics of the C‑Terminal Region of Human Desmoplakin
journal contribution
posted on 2016-05-17, 00:00 authored by Charles
E. McAnany, Cameron MuraMulticellular
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 traffic
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 (DPCTT). Using molecular dynamics simulations,
we have elucidated the structural basis of these PTM-induced effects.
Our simulations, nearing 2 μs in aggregate, indicate that phosphorylation
of S2849 induces an “arginine claw” in desmoplakin’s
C-terminal tail. 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 overall
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.