Plakophilin 1 but not plakophilin 3 regulates desmoglein clustering


Plakophilins (Pkp) are desmosomal plaque proteins crucial for desmosomal adhesion and participate in the regulation of desmosomal turnover and signaling. However, direct evidence that Pkps regulate clustering and molecular binding properties of desmosomal cadherins is missing. Here, keratinocytes lacking either Pkp1 or 3 in comparison to wild type (wt) keratinocytes were characterized with regard to their desmoglein (Dsg) 1- and 3-binding properties and their capability to induce Dsg3 clustering. As revealed by atomic force microscopy (AFM), both Pkp-deficient keratinocyte cell lines showed reduced membrane availability and binding frequency of Dsg1 and 3 at cell borders. Extracellular crosslinking and AFM cluster mapping demonstrated that Pkp1 but not Pkp3 is required for Dsg3 clustering. Accordingly, Dsg3 overexpression reconstituted cluster formation in Pkp3- but not Pkp1-deficient keratinocytes as shown by AFM and STED experiments. Taken together, these data demonstrate that both Pkp1 and 3 regulate Dsg membrane availability, whereas Pkp1 but not Pkp3 is required for Dsg3 clustering.

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Fig. 1
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Fig. 5



Atomic force microscopy


Arrhythmogenic cardiomyopathy








Extracellular domains


Fluorescence recovery after photobleaching


Cultured human keratinocytes


Intermediate filament


Mitogen-activated protein kinase


Murine keratinocytes








Pemphigus vulgaris


Quantitative imaging


Stimulated emission depletion


Ethylene glycolbis (sulfosuccinimidylsuccinate)


Unbinding forces


Unbinding position


Wild type


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We thank Andrea Wehmeyer and Sabine Mühlsimer for excellent technical assistance and JPK instruments and Sunil Yeruva for constructive technical and scientific discussion. The project is funded by Else-Kröner-Fresenius-Stiftung 2016_AW157 to FV and JW and DFG SPP1782 to JW.

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MFu, MF, MR, DK: methodology, data acquisition and analysis; FV and JW: funding acquisition, conceptualization and supervision; MFu, FV, JW: writing and editing, RK, MH, VS: methodology, review.

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Correspondence to Jens Waschke or Franziska Vielmuth.

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Fuchs, M., Foresti, M., Radeva, M.Y. et al. Plakophilin 1 but not plakophilin 3 regulates desmoglein clustering. Cell. Mol. Life Sci. 76, 3465–3476 (2019).

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  • Desmosome
  • Cell adhesion
  • Desmosomal clustering
  • Atomic force microscopy
  • STED