Abstract
Envoplakin, periplakin and desmoplakin are cytoskeletal proteins that provide structural integrity within the skin and heart by resisting shear forces. Here we reveal the nature of unique hinges within their plakin domains that provides divergent degrees of flexibility between rigid long and short arms composed of spectrin repeats. The range of mobility of the two arms about the hinge is revealed by applying the ensemble optimization method to small-angle X-ray scattering data. Envoplakin and periplakin adopt ‘L’ shaped conformations exhibiting a ‘helicopter propeller’-like mobility about the hinge. By contrast desmoplakin exhibits essentially unrestricted mobility by ‘jack-knifing’ about the hinge. Thus the diversity of molecular jointing that can occur about plakin hinges includes ‘L’ shaped bends, ‘U’ turns and fully extended ‘I’ orientations between rigid blocks of spectrin repeats. This establishes specialised hinges in plakin domains as a key source of flexibility that may allow sweeping of cellular spaces during assembly of cellular structures and could impart adaptability, so preventing irreversible damage to desmosomes and the cell cytoskeleton upon exposure to mechanical stress.
Highlights
The plakin family of proteins connect the intermediate filaments that form the cell cytoskeleton to cadherin-mediated cell-cell junctions, and must be able to withstand mechanical stresses to provide integrity to tissues [1,2]
We recently showed that the entire plakin domain from desmoplakin forms a non-linear shape in solution, with a long arm comprised of SR3-6 linked with a short arm comprised of SR7-8 [21]
While most spectrin repeats and single Src homology 3 (SH3) domain are highly conserved (Fig. 2), the sequence alignments revealed that SR6 is absent in all envoplakin and periplakin paralogues, and that the hinge connecting to SR7 is divergent
Summary
The plakin family of proteins connect the intermediate filaments that form the cell cytoskeleton to cadherin-mediated cell-cell junctions, and must be able to withstand mechanical stresses to provide integrity to tissues [1,2]. We show that the plakin domains of envoplakin, periplakin and desmoplakin display distinct conformations, and define their distinct ranges of available flexibility.
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