Sprecher E, Ishida-Yamamoto A, Becker O M, Marekov L, Miller C J, Steinert P M, Neldner K, Richard G
Department of Dermatology and Cutaneous Biology and the Jefferson Institute of Molecular Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
J Invest Dermatol. 2001 Apr;116(4):511-9. doi: 10.1046/j.1523-1747.2001.01292.x.
Unraveling the molecular basis of inherited disorders of epithelial fragility has led to understanding of the complex structure and function of keratin intermediate filaments. Keratins are organized as a central alpha-helical rod domain flanked by nonhelical, variable end domains. Pathogenic mutations in 19 different keratin genes have been identified in sequences corresponding to conserved regions at the beginning and end of the rod. These areas have been recognized as zones of overlap between aligned keratin proteins and are thought to be crucial for proper assembly of keratin intermediate filaments. Consequently, all keratin disorders of skin, hair, nail, and mucous membranes caused by mutations in rod domain sequences are characterized by perinuclear clumping of fragmented keratin intermediate filaments, thus compromising mechanical strength and cell integrity. We report here the first mutation in a keratin gene (KRT1) that affects the variable tail domain (V2) and results in a profoundly different abnormality of the cytoskeletal architecture leading to a severe form of epidermal hyperkeratosis known as ichthyosis hystrix Curth-Macklin. Structural analyses disclosed a failure in keratin intermediate filament bundling, retraction of the cytoskeleton from the nucleus, and failed translocation of loricrin to the desmosomal plaques. These data provide the first in vivo evidence for the crucial role of a keratin tail domain in supramolecular keratin intermediate filament organization and barrier formation.
揭示上皮脆弱性遗传性疾病的分子基础，有助于理解角蛋白中间丝的复杂结构和功能。角蛋白由一个中央α-螺旋杆状结构域组成，两侧是非螺旋的可变末端结构域。在与杆状结构域起始和末端保守区域相对应的序列中，已鉴定出19种不同角蛋白基因的致病突变。这些区域被认为是对齐的角蛋白蛋白之间的重叠区域，并且被认为对角蛋白中间丝的正确组装至关重要。因此，由杆状结构域序列突变引起的所有皮肤、头发、指甲和粘膜的角蛋白疾病，其特征是破碎的角蛋白中间丝在核周聚集，从而损害机械强度和细胞完整性。我们在此报告角蛋白基因（KRT1）中的首个突变，该突变影响可变尾部结构域（V2），并导致细胞骨架结构出现截然不同的异常，从而导致一种严重的表皮角化过度形式，即Curth-Macklin型豪猪状鱼鳞病。结构分析揭示了角蛋白中间丝束形成失败、细胞骨架从细胞核回缩以及兜甲蛋白未能转运至桥粒斑。这些数据首次在体内证明了角蛋白尾部结构域在超分子角蛋白中间丝组织和屏障形成中的关键作用。
