Hopkinson S B, Findlay K, deHart G W, Jones J C
Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Invest Dermatol. 1998 Dec;111(6):1015-22. doi: 10.1046/j.1523-1747.1998.00452.x.
The hemidesmosome is a multimolecular complex that integrates the extracellular matrix with the keratin cytoskeleton and that stabilizes epithelial attachment to connective tissue. A 180 kDa protein (BP180, type XVII collagen), first identified by its reactivity with autoantibodies in the serum of patients with a blistering skin disease called bullous pemphigoid (BP), is a transmembrane component of the hemidesmosome with a collagen-like extracellular domain. Here, using recombinantly expressed molecules and the yeast two-hybrid assay, we have identified alpha6 integrin as a BP180-binding partner. The association between specific domains of the BP180 and alpha6 integrin molecules is inhibited by a 14 mer peptide, whose sequence is identical to amino acid residues 506-519 in the noncollagenous region of the ectodomain of the BP180 molecule, as well as by antibodies raised against this peptide. The 14 mer peptide sequence is part of an epitope recognized by autoantibodies that are pathogenic in BP. In vivo, when 804G cells are plated into medium containing the same peptide, they fail to assemble hemidesmosomes. Furthermore, although BP180 and certain cytoplasmic components of the hemidesmosome colocalize in the peptide-treated cells, they are aberrantly distributed and fail to show extensive association with (alpha6beta4 integrin. Taken together, our results indicate that BP180 is a novel transmembrane ligand of the alpha6beta4 integrin heterodimer. In addition, our data provide support for the possibility that BP180 and alpha6 integrin interaction is not only mediated by the BP epitope but is necessary for hemidesmosome formation.
半桥粒是一种多分子复合物，它将细胞外基质与角蛋白细胞骨架整合在一起，并稳定上皮细胞与结缔组织的附着。一种180 kDa的蛋白质（BP180，XVII型胶原蛋白），最初是通过其与一种名为大疱性类天疱疮（BP）的水疱性皮肤病患者血清中的自身抗体的反应性而被鉴定出来的，它是半桥粒的跨膜成分，具有类似胶原蛋白的细胞外结构域。在这里，我们使用重组表达分子和酵母双杂交试验，鉴定出α6整合素是BP180的结合伴侣。BP180的特定结构域与α6整合素分子之间的结合被一种14肽抑制，该肽的序列与BP180分子胞外结构域非胶原蛋白区域中的506 - 519位氨基酸残基相同，以及被针对该肽产生的抗体抑制。14肽序列是BP中致病自身抗体识别的表位的一部分。在体内，当将804G细胞接种到含有相同肽的培养基中时，它们无法组装半桥粒。此外，尽管BP180和半桥粒的某些细胞质成分在经肽处理的细胞中共定位，但它们分布异常，并且未能显示出与α6β4整合素广泛结合。综上所述，我们的结果表明BP180是α6β4整合素异二聚体的一种新型跨膜配体。此外，我们的数据支持了BP180与α6整合素相互作用不仅由BP表位介导，而且对半桥粒形成是必需的这一可能性。
