Desmosome

The desmosome (macula adherens, from the Greek desmos, "bond," and soma, "body") is a specialized disk-shaped intercellular adhesive junction that tethers the intermediate filament cytoskeletons of adjacent cells into a continuous, mechanically resilient transcellular network. Whereas adherens junctions and tight junctions link to the cortical actin cytoskeleton and form continuous circumferential belts around polarized epithelial cells, desmosomes form discrete spot-welds (0.2–0.5 μm in diameter) that are most abundant in tissues subjected to intense mechanical shear and tensile stress, including stratified squamous epidermis, oral mucosa, and the intercalated discs of vertebrate cardiac muscle.

Ultrastructurally, a mature desmosome exhibits a symmetrical bipartite organization across a 30–35 nm intercellular space bisected by an electron-dense central midline (desmoglea). On the cytoplasmic face of each opposing plasma membrane lies a bipartite electron-dense plaque—composed of an outer dense plaque (ODP) (15–20 nm thick) abutting the membrane and an inner dense plaque (IDP) (15–20 nm separated from the ODP)—into which keratin (in epithelia), desmin (in cardiomyocytes), or vimentin (in arachnoid meninges and follicular dendritic cells) intermediate filaments loop and anchor.

Desmosomes are assembled from three evolutionary protein families: desmosomal cadherins, armadillo-repeat plaque proteins, and plakin cytolinkers:

1. Desmosomal Cadherins: Desmogleins and Desmocollins

Encoded in a tightly linked gene cluster on human chromosome 18q12.1, the seven human desmosomal cadherins comprise four desmogleins (DSG1–DSG4) and three desmocollins (DSC1–DSC3). Like classical cadherins, their ectodomains consist of four extracellular cadherin repeats (EC1–EC4) and an extracellular anchor (EA) domain connected by hinge regions that coordinate three Ca²⁺ ions per linker (12 Ca²⁺ ions per ectodomain) to rigidify the curved rod-like ectodomain:

• Heterophilic Trans-Adhesion: In the presence of extracellular Ca²⁺ (~1.2–1.5 mM), the N-terminal EC1 domains of opposing cells undergo a strand-swap dimerization, inserting a conserved Trp2 side chain into the hydrophobic acceptor pocket (containing Ala80) of the partner cadherin across the midline. Cryo-electron tomography and biophysical force spectroscopy demonstrate that heterophilic Dsg:Dsc dimers bind with higher affinity than homophilic dimers and form an ordered, quasi-periodic two-dimensional lattice along the central midline.
• Isoform Stratification in Epidermis: Expression of desmosomal cadherins is spatially graded across epidermal differentiation layers: DSG2 and DSC2 are expressed ubiquitously in simple epithelia and cardiomyocytes; DSG3 and DSC3 dominate the proliferative basal layer (stratum basale) of stratified squamous epithelia; and DSG1 and DSC1 dominate the upper spinous and granular layers (stratum spinosum and stratum granulosum).

2. Armadillo Plaque Proteins: Plakoglobin and Plakophilins

The cytoplasmic tails of desmogleins and desmocollins (the intracellular cadherin-like segment, ICS, and desmoglein-specific repeat domains) recruit two classes of armadillo-repeat proteins within the outer dense plaque:

• Plakoglobin (JUP, γ-catenin): Contains 12 central armadillo repeats flanked by N- and C-terminal domains. Plakoglobin is the only junctional protein shared between both desmosomes and adherens junctions, where it bridges the ICS domain of desmosomal cadherins directly to the N-terminal plakin domain of desmoplakin.
• Plakophilins (PKP1, PKP2, PKP3): Contain 9 central armadillo repeats with a flexible bend between repeats 5 and 6. PKP1 stabilizes keratin filament recruitment in suprabasal epidermis; PKP2 is the sole plakophilin isoform expressed in the adult mammalian heart, where it scaffolds desmoplakin, connexin-43 gap junctions, and Na_V1.5 voltage-gated sodium channels at the cardiac area composita.

3. Desmoplakin: The Obligate Intermediate-Filament Cytolinker

Desmoplakin (DSP), the largest and most abundant component of the desmosomal plaque (existing as a 332 kDa DSP I isoform and an alternatively spliced 260 kDa DSP II isoform), forms a homodimer with a central coiled-coil rod domain:

• Its globular N-terminal plakin domain (composed of spectrin-like repeats and an SH3 domain) resides in the ODP and binds plakoglobin and plakophilins.
• Its globular C-terminal domain projects into the IDP and contains three plakin repeat domains (PRDs A, B, and C) and a glycine-serine-arginine (GSR) tail that bind directly to the coiled-coil rod domains of keratin (in epithelia) or desmin (in cardiac muscle).

When epithelial cells are newly confluent or actively migrating during wound healing, their desmosomes exist in a Ca²⁺-dependent adhesive state: chelation of extracellular Ca²⁺ with EGTA causes rapid dissociation of the cadherin midline and internalization of half-desmosomes. In intact mature tissues, however, desmosomes transition into a specialized, high-strength Ca²⁺-independent "hyper-adhesive" state discovered by David Garrod:

1. Structural Basis of Hyper-Adhesion: Ordered packing of the extracellular EC1–EC4 cadherin lattice locks the Ca²⁺ ions into their interdomain coordination pockets so tightly that even prolonged incubation in Ca²⁺-free chelating media cannot extract them or split the desmosome.
2. Protein Kinase Cα (PKCα) Switch: Upon epithelial wounding, growth factor signaling activates PKCα, which translocates to the desmosomal plaque and phosphorylates desmoplakin (and regulatory sites in the C-terminal GSR domain at Ser2849 in cooperation with GSK-3β), rapidly converting hyper-adhesive desmosomes back into a dynamic, Ca²⁺-dependent state that permits keratinocyte sheet migration across the wound bed.

Because desmosomes provide the primary mechanical load-bearing linkages in skin and heart muscle, autoimmune or genetic disruption of any tier of the desmosomal complex produces pronounced blistering dermatoses or lethal cardiac arrhythmias:

The Desmoglein Compensation Hypothesis

Formulated by John Stanley and Masayuki Amagai, the desmoglein compensation hypothesis explains the distinct anatomical blister planes of pemphigus vulgaris, pemphigus foliaceus, and staphylococcal scalded skin syndrome (SSSS):

• In mucous membranes, DSG3 is expressed at high levels throughout all epithelial layers while DSG1 is minimally expressed. Consequently, anti-Dsg1 autoantibodies (in pemphigus foliaceus) or S. aureus exfoliative toxins (which selectively cleave Dsg1 between EC3 and EC4 at Glu381) leave mucosal epithelia intact because DSG3 compensates.
• In the superficial granular layer of the epidermis, DSG1 is expressed alone without DSG3; therefore, loss of DSG1 produces superficial subcorneal splitting.
• Conversely, in mucosal-dominant pemphigus vulgaris, anti-Dsg3 autoantibodies destroy adhesion in the basal/suprabasal mucosa (where DSG1 is absent), causing pronounced oral erosions; when patients develop both anti-Dsg3 and anti-Dsg1 autoantibodies (mucocutaneous PV), compensation fails across both tissues, producing widespread suprabasal blistering of skin and mucosa (acantholysis with "tombstone" basal keratinocytes remaining attached to the basement membrane via hemidesmosomes).

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