EXPRESSION, STRUCTURE AND FUNCTION OF FILAGGRIN

聚丝蛋白是一种主要的终末分化产物， 分化哺乳动物表皮细胞，这被认为是 参与角蛋白的聚集和特定排列 在分化的最后阶段的中间丝。 因此 聚丝蛋白是一个重要的例子， proteins. 我们已经分离了cDNA和基因组克隆，它们表明， 丝聚蛋白最初表达为大的多蛋白前体， 丝聚蛋白，其随后被蛋白水解加工成 单个功能性聚丝蛋白分子。 在人类系统中， 前体由3个等位基因大小变体组成，含有10、11或12个 由正常孟德尔遗传机制分离的串联重复序列。 此外，这些重复序列显示出相当大的序列变异， 任何两个重复序列彼此之间只有大约85%的同源性;到目前为止，我们 发现在丝聚蛋白重复序列的324个氨基酸残基中， 40%的位置是可变的。 我们构建了基因组 用于生产转基因小鼠的片段。 我们已经开始了 控制表达的调节序列的系统分析 这个基因系统。 我们正在研究相互作用的方法， 通过使用固态NMR具有角蛋白中间丝的聚丝蛋白 技术. 由于有许多角质化疾病的 皮肤，有一些证据涉及不正确的表达， 原丝聚蛋白基因，我们已经开始了系统的搜索， 丝聚蛋白在角化遗传病中的可能作用。

Filaggrin is a major differentiation product of terminally differentiating mammalian epidermal cells, that is thought to be involved in the aggregation and specific alignment of keratin intermediate filaments during the final stages of differentiation. Thus filaggrin is an important example of an intermediate filament-associated proteins. We have isolated both cDNA and genomic clones which show that filaggrin is initially expressed as a large polyprotein precursor, filaggrin, that is subsequently proteolytically processed into individual functional filaggrin molecules. In the human system, the precursor consists of 3 allelic size variants, containing 10, 11 or 12 tandem repeats that segregated by normal Mendelian genetic mechanisms. In addition, these repeats show considerable sequence variation, so that any two repeats are only about 85% homologous to each other; so far, we find that of the 324 amino acid residues of the filaggrin repeats, about 40% of the positions are variable. We have constructed genomic fragments for the production of transgenic mice. We have begun a systematic analysis of regulatory sequences that control the expression of this gene system. We are studying the method of interaction of filaggrin with keratin intermediate filaments by use of solid state NMR techniques. Since there are a number of keratinizing disorders of the skin for which there is some evidence involving incorrect expression of the profilaggrin gene, we have begun a systematic search for the possible role of filaggrin in genetic diseases of keratinization.