Supramolecular Interactions in the Dermo-epidermal Junction Zone

Abstract

The dermis and the epidermis of normal human skin are functionally separated by a basement membrane but, together, form a stable structural continuum. Anchoring fibrils reinforce this connection by insertion into the basement membrane and by intercalation with banded collagen fibrils of the papillary dermis. Structural abnormalities in collagen VII, the major molecular constituent of anchoring fibrils, lead to a congenital skin fragility condition, dystrophic epidermolysis bullosa, associated with skin blistering. Here, we characterized the molecular basis of the interactions between anchoring fibrils and banded collagen fibrils. Suprastructural fragments of the dermo-epidermal junction zone were generated by mechanical disruption and by separation with magnetic Immunobeads. Anchoring fibrils were tightly attached to banded collagen fibrils. In vitro binding studies demonstrated that a von Willebrand factor A-like motif in collagen VII was essential for binding of anchoring fibrils to reconstituted collagen I fibrils. Since collagen I and VII molecules reportedly undergo only weak interactions, the attachment of anchoring fibrils to collagen fibrils depends on supramolecular organization of their constituents. This complex is stabilized in situ and resists dissociation by strong denaturants.The functions and homeostasis of skin critically depend on the stable organization and cohesion between the epidermis and the dermis. These tissue layers are confined and interconnected by the dermo-epidermal junction zone (DEJZ) 4 , which comprises the basal keratinocytes, the dermo-epidermal basement membrane, and the uppermost, i.e. the papillary dermis.The suprastructural entity affording pivotal mechanical stability of the DEJZ is the anchoring complex, which sequentially consists of the hemidesmosomes at the basal surface of the keratinocytes, the anchoring filaments linking the hemidesmosomes to the basement membrane, and the anchoring fibrils connecting the basement membrane with the underlying dermal stroma (1). Anchoring fibrils are centro-symmetrically banded structures that originate in the basement membrane and either end in the papillary dermis or loop back into the basement membrane (2-4). Their calculated length is 785 nm (5), but they appear shorter in the tissue due to their insertion into the lamina densa (3, 6).The quantitatively major molecular constituent of anchoring fibrils is collagen VII (7). The major component of D-periodically banded, dermal collagen fibrils, collagen I, copolymerizes with minor quantities of collagens III, V, XII, and XIV to form macromolecular alloys that vary in their composition and, because of this, also in their supramolecular organization. Therefore, the latter collagens may contribute only small mass fractions, yet critically determine the structural and functional properties of the fibrils (8 -10).Structural abnormalities of the anchoring complex lead to skin fragility, the landmark of epidermolysis bullosa, a group of heritable blistering skin diseases (11). The absenc...

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The radial growth phase of malignant melanoma: multi-phase modelling, numerical simulations and linear stability analysis

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Amlexanox Enhances Premature Termination Codon Read-Through in COL7A1 and Expression of Full Length Type VII Collagen: Potential Therapy for Recessive Dystrophic Epidermolysis Bullosa

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