EXPRESSION, STRUCTURE AND FUNCTION OF FILAGGRIN

微丝蛋白是终末分化的主要分化产物。 哺乳动物的表皮细胞，被认为参与了 角蛋白中间丝的聚集和特异性排列 分化的最后阶段。因此，Filaggrin是一个重要的例子 一种中间的细丝相关蛋白。我们已经分离了这两个基因 以及基因组克隆，这些克隆表明微丝蛋白最初表达为 大的多聚蛋白前体，微丝蛋白，随后是 蛋白水解物加工成单独的功能性微丝蛋白分子。 在人类系统中，前体由3个等位基因大小变异组成， 包含由正常孟德尔基因分离的10、11或12个串联重复序列 遗传机制。此外，这些重复序列显示出相当大的序列 变异，因此任何两个重复与每个重复只有大约85%的同源性 到目前为止，我们发现在微丝蛋白的324个氨基酸残基中 重复，大约40%的位置是可变的。我们已经建造了 用于生产转基因小鼠的基因组片段。我们已经开始了一场 对调控基因表达的调控序列进行系统分析 这个基因系统。我们正在研究细丝研磨相互作用的方法。 通过使用固体核磁共振技术与角蛋白中间丝结合。 因为有许多皮肤角化性疾病， 有一些证据涉及Profilaggrin的错误表达 基因，我们已经开始系统地研究微丝蛋白的可能作用 角质化的遗传性疾病。

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 protein. 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.