Interaction of BP180 (type XVII collagen) and alpha 6 integrin is necessary for stabilization of hemidesmosome structure

The hemidesmosome is a multimolecular complex that integrates the extracell ular matrix with the keratin cytoskeleton and that stabilizes epithelial at tachment to connective tissue. A 180 kDa protein (BP180, type XVII collagen ), first identified by its reactivity with autoantibodies in the serum of p atients with a blistering skin disease called bullous pemphigoid (BP), is a transmembrane component of the hemidesmosome with a collagen-like extracel lular domain. Here, using recombinantly expressed molecules and the yeast t wo-hybrid assay, we have identified alpha 6 integrin as a BP180-binding par tner. The association between specific domains of the BP180 and alpha 6 int egrin molecules is inhibited by a 14 mer peptide, whose sequence is identic al to amino acid residues 506-519 in the noncollagenous region of the ectod omain of the BP180 molecule, as well as by antibodies raised against this p eptide. The 14 mer peptide sequence is part of an epitope recognized by aut oantibodies that are pathogenic in BP. In vivo, when 804G cells are plated into medium containing the same peptide, they fail to assemble hemidesmosom es, Furthermore, although BP180 and certain cytoplasmic components of the h emidesmosome colocalize in the peptide-treated cells, they are aberrantly d istributed and fail to show extensive association with alpha 6 beta 4 integ rin, Taken together, our results indicate that BP180 is a novel transmembra ne ligand of the alpha 6 beta 4 integrin heterodimer. In addition, our data provide support for the possibility that BP180 and alpha 6 integrin intera ction is not only mediated by the BP epitope but is necessary for hemidesmo some formation.