The trimeric transmembrane collagen BP180, also known as collagen XVII, is an essential component of hemidesmosomes at the dermal–epidermal junction and connects the cytoplasmic keratin network to the extracellular basement membrane. Dysfunction of BP180 caused by mutations in patients with junctional epidermolysis bullosa or autoantibodies in those with bullous pemphigoid leads to severe skin blistering. The extracellular collagenous domain of BP180 participates in the protein’s triple-helical folding, but the structure and functional importance of the intracellular domain (ICD) of BP180 are largely unknown. In the present study, we purified and characterized human BP180 ICD. When expressed in Escherichia coli as glutathione-S-transferase or 6 × histidine tagged fusion protein, the BP180 ICD was found to exist as a monomer. Analysis of the secondary structure content by circular dichroism spectroscopy revealed that the domain is intrinsically disordered. This finding aligned with that of a bioinformatic analysis, which predicted a disordered structure. Interestingly, both anionic detergent micelles and lipid vesicles induced partial folding of the BP180 ICD, suggesting that in its natural environment, the domain’s folding and unfolding may be regulated by interaction with the cell membrane or accompanying proteins. We hypothesize that the intrinsically disordered structure of the ICD of BP180 contributes to the mechanism that allows the remodeling of hemidesmosome assembly.

中文翻译：

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BP180/XVII 胶原蛋白的胞内结构域本质上是无序的，并且在阴离子膜脂质模拟环境中部分折叠。


三聚体跨膜胶原蛋白 BP180，也称为胶原蛋白 XVII，是真皮-表皮交界处半桥粒的重要组成部分，并将细胞质角蛋白网络与细胞外基底膜连接起来。大疱性交界性表皮松解症患者的突变或大疱性类天疱疮患者的自身抗体引起的 BP180 功能障碍会导致严重的皮肤起泡。 BP180 的细胞外胶原结构域参与蛋白质的三螺旋折叠，但 BP180 的细胞内结构域 (ICD) 的结构和功能重要性很大程度上未知。在本研究中，我们纯化并表征了人类 BP180 ICD。当在大肠杆菌中表达为谷胱甘肽-S-转移酶或 6 × 组氨酸标记融合蛋白时，发现 BP180 ICD 以单体形式存在。通过圆二色光谱分析二级结构含量表明该结构域本质上是无序的。这一发现与生物信息学分析的结果一致，生物信息学分析预测了无序的结构。有趣的是，阴离子去污剂胶束和脂质囊泡均诱导 BP180 ICD 的部分折叠，这表明在其自然环境中，该结构域的折叠和展开可能通过与细胞膜或伴随蛋白的相互作用来调节。我们假设 BP180 的 ICD 本质上无序的结构有助于半桥粒组装的重塑机制。