ORGANIZATION, STRUCTURE, AND POLYMORPHISMS OF THE HUMAN PROFILAGGRIN GENE
ORGANIZATION, STRUCTURE, AND POLYMORPHISMS OF THE HUMAN PROFILAGGRIN GENE
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DOI：
10.1021/bi00492a018
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发表时间：
1990-10-09
期刊：
影响因子：
2.9
通讯作者：
STEINERT, PM
中科院分区：
文献类型：
--
作者：
GAN, SQ;MCBRIDE, OW;STEINERT, PM
聚丝蛋白原是哺乳动物表皮透明角质颗粒的主要蛋白质组分。它最初表达为大的多蛋白前体，随后被蛋白水解加工成单个功能性聚丝蛋白分子。我们已经分离了编码人基因和mRNA的5“-和3”-末端的基因组DNA和cDNA克隆。这些数据揭示了可能存在的“CAT”和“TATA”序列，在5“-非翻译区的内含子，和几个潜在的调控序列。虽然所有重复序列的长度相同（972 bp，324个氨基酸），但同一克隆上的重复序列之间和不同克隆之间的序列显示出相当大的变异（10-15%）。大多数变异可归因于单碱基的变化，但也有许多变异涉及电荷的变化。因此，人聚丝蛋白由不同大小、电荷和序列的分子的异质群体组成。然而，编码氨基和羧基末端的氨基酸序列更保守，基因编码部分侧翼的5“和3”DNA序列也是如此。在这些保守的侧翼序列中存在独特的限制酶位点，使得能够计算全长基因的大小和其中的重复序列的数量：根据基因组DNA的来源，该基因包含10、11或12个聚丝蛋白重复序列，这些重复序列通过正常的孟德尔遗传机制在家族中分离。这意味着由于不同个体之间的简单等位基因差异，人聚丝蛋白原基因系统在大小方面也是多态的。聚丝蛋白原的氨基末端和羧基末端序列含有部分或截短的重复序列，在末端具有不寻常的非聚丝蛋白样序列。这样的序列让人想起在其他结构蛋白系统中遇到的前肽。我们认为，这些序列是所需的组装积累的蛋白质成大的透明角质颗粒之间的角蛋白丝在颗粒细胞和援助在以后的处理事件。
Profilaggrin is a major protein component of the keratohyalin granules of mammalian epidermis. It is initially expressed as a large polyprotein precursor and is subsequently proteolytically processed into individual functional filaggrin molecules. We have isolated genomic DNA and cDNA clones encoding the 5''- and 3''-ends of the human gene and mRNA. The data reveal the presence of likely "CAT" and "TATA" sequences, an intron in the 5''-untranslated region, and several potential regulatory sequences. While all repeats are of the same length (972 bp, 324 amino acids), sequences display considerable variation (10-15%) between repeats on the same clone and between different clones. Most variations are attributable to single-base changes, but many also involve changes in charge. Thus, human filaggrin consists of a heterogeneous population of molecules of different sizes, charges, and sequences. However, amino acid sequences encoding the amino and carboxyl termini are more conserved, as are the 5'' and 3'' DNA sequences flanking the coding portions of the gene. The presence of unique retriction enzyme sites in these conserved flanking sequences had enabled calculations on the size of the full-length gene and the numbers of repeats in it: depending on the source of genomic DNA, the gene contains 10, 11, or 12 filaggrin repeats that segregate in kindred families by normal Mendelian genetic mechanisms. This means that the human profilaggrin gene system is also polymorphic with respect to size due to simple allelic differences between different individuals. The amino- and carboxyl-terminal sequences of profilaggrin contain partial or truncated repeats with unusual un-filaggrin-like sequences on the termini. Such sequences are reminiscent of propeptides encountered in other structural protein systems. We suggest these seqeunces are required for the assembly of the accumulating protein into large keratohyalin granules among the keratin filaments in the granular cells and aid in later processing events.