Type VII collagen, anchoring fibrils, and epidermolysis bullosa

Abstract

The anchoring fibrils at the dermal-epidermal junction have been well characterized as ultrastructural entities. From their appearance, it was proposed that they fortified the attachment of the epidermis to the dermis. This hypothesized function was strengthened by observations indicating that the anchoring fibrils were abnormal, diminished, or absent from individuals with dystrophic epidermolysis bullosa. Therefore, characterization of the molecular constituents of the anchoring fibrils and their interactions with other basement membrane and dermal components might lead to identification of the gene defects underlying at least some forms of epidermolysis bullosa. Type VII collagen was identified as the protein component of anchoring fibrils in 1986. Since then, the major characteristics of the molecule have been described. These are consistent with a model wherein secreted type VII collagen molecules form disulfide-bond stabilized antiparallel dimers. The dimers then condense laterally into unstaggered arrays that are the anchoring fibrils. This arrangement allows for the protrusion of large globular domains (NC-1) from both ends of the fibrils. The aggregated triple-helical domains extend into the papillary dermis and entrap fibrous dermal components. The NC-1 domains are believed to interact with components of the basement membrane and thus to mediate the attachment of the basement membrane to the dermis. This model predicts that mutations in the type VII collagen gene that prevent the secretion of the molecule will be the most devastating, whereas mutations in the regions encoding the globular domains may show more variable phenotype. Ultimately, understanding the function of type VII collagen at the molecular level will be the key to devising strategies to moderate the pathophysiology of dystrophic epidermolysis bullosa.