Major high molecular weight protein of desmosomes. Involved in the organization of the desmosomal cadherin-plakoglobin complexes into discrete plasma membrane domains and in the anchoring of intermediate filaments to the desmosomes. Homodimer. Interacts with COL17A1 (via cytoplasmic region). Associates (via C-terminal) with KRT5-KRT14 (via rod region), KRT8-KRT18 and VIM intermediate filaments. Interacts with PKP2 (By similarity). Interacts weakly with TMEM65 (PubMed:26403541). Innermost portion of the desmosomal plaque. Colocalizes with epidermal KRT5-KRT14 and simple KRT8-KRT18 keratins and VIM intermediate filaments network (By similarity). Localizes at the intercalated disk in cardiomyocytes (PubMed:26403541). Its association with epidermal and simple keratins is dependent on the tertiary structure induced by heterodimerization of these intermediate filaments proteins and most likely involves recognition sites located in the rod domain of these keratins. The N-terminal region is required for localization to the desmosomal plaque and interacts with the N-terminal region of plakophilin 1. The three tandem plakin repeat regions in the C-terminus mediate binding to intermediate filaments. Ser-2860 is probably phosphorylated by a cAMP-dependent protein kinase. Phosphorylation on Ser-2860 probably affects its association with epidermal, simple cytokeratins and VIM intermediate filaments (By similarity). Substrate of transglutaminase. Some glutamines and lysines are cross-linked to other desmoplakin molecules, to other proteins such as keratin, envoplakin, periplakin and involucrin, and to lipids like omega-hydroxyceramide (By similarity). Belongs to the plakin or cytolinker family.