The 180-kD
bullous pemphigoid autoantigen (BP180) is a component of the hemidesmosome, a cell-matrix connector. This
protein is oriented in a type II fashion in the membrane of the hemidesmosome and is a hybrid
collagen (classified as type XVII). We have analyzed the fate of various mutant BP180 molecules transfected into several different cell types. A
protein, D1, lacking the
collagen-like extracellular domains of BP180 polarizes normally in 804G epithelial cells and colocalizes with other hemidesmosomal components in the plane of the basal cell surface. However, deletion of a stretch of 36
amino acids located at the NH2 terminus of D1 induces an apical polarization of the
protein (D1-36N) in the cell surface of 804G cells. Deletion of the 27-amino
acid noncollagenous extracellular domain that is located immediately after the membrane spanning domain of BP180 results in a failure of D1-27C
protein to codistribute with other hemidesmosomal components despite its basal localization in transfected 804G cells. In FG cells, which lack their own BP180, transfected D1
protein localizes with the
alpha 6 beta 4 integrin heterodimer. In HT1080 cells, which do not possess BP180 or beta 4
integrin, D1
protein localizes with
alpha 6 beta 1 integrin while both the D1-27C and D1-36N
proteins do not. Moreover, D1
protein coprecipitates with
alpha 6 integrin from extracts of HT1080 transfectants. Taken together, these results suggest that the NH2-terminal domain of BP180 determines polarization of BP180 while the noncollagenous extracellular domain of BP180 stabilizes its interactions with other hemidesmosomal components, such as
alpha 6 integrin. Perturbation of this latter domain by human
bullous pemphigoid autoantibodies may explain the loss of epidermal cell-dermis attachment that characterizes the BP disease.