Desmoplakin (DSP), a cytolinker of the plakin family, mediates the connection of intermediate filaments (IFs) to desmosomes in epithelia and cardiac muscle cells through its C-terminal tail domains (DSP-CT). Mutations in DSP cause skin fragility syndromes, palmo-plantar keratoderma and/or cardiomyopathy. To gain better insight into the DSP-IF association and the functional impact of mutations in DSP-CT we have characterized the interaction of DSP with epidermal cytokeratins and muscle-specific IF protein desmin. The results indicate that DSPCT has a high affinity for bona fide IFs. It predominantly interacts with the coil 1 of heteromeric epidermal K1/K10 and K5/K14 and homomeric desmin. Four of eight analyzed amino acid substitutions in DSP-CT, considered as potentially pathogenic, variably inhibited DSP binding to both cytokeratins and desmin. Based on our findings, we postulate that
DSP-CT associates with various IFs by means of major recognition sites contained in the conserved coil 1 of IFs and its high affinity for IFs is due to the contribution of several IF-binding domains. In agreement with this model, mutations in DSP-CT, linked to skin pathologies, almost invariably also affect DSP-desmin interaction important for maintenance of cardiac cytoarchitecture and are therefore expected to ultimately lead to cardiomyopathy.

Characterization of the interaction of desmoplakin with keratins and desmin: implication for genetic cardio-cutaneous syndromes