DiLella A G, Craig R J
Department of Molecular Genetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
Biochemistry. 1991 Sep 3;30(35):8512-7. doi: 10.1021/bi00099a002.
FKBP-12, the major T-cell binding protein for the immunosuppressive agents FK506 and rapamycin, catalyzes the interconversion of the cis and trans rotamers of the peptidyl-prolyl amide bond of peptide and protein substrates. The function of rotamase activity in cells and the role of FKBP-12 in immunoregulation is uncertain. In this paper we report the cloning and characterization of the human chromosomal FKBP-12 gene and four processed FKBP-12 pseudogenes. The FKBP-12 gene is 24 kilobases in length and contains five exons. The protein-coding region of the gene is divided into four exon modules that correlate with the structural and functional domains of the protein. The novel structure of FKBP-12 resulting from the topology of the antiparallel beta-sheet is the topological crossing of two loops that are encoded by separate exons. Separate exons also encode the antiparallel beta-sheet and alpha-helical region that define the drug-binding pocket and enzyme activity site of FKBP-12. The exon organization of the FKBP-12 gene also provided insight into the genetic evolution of the immunophilin family. Knowledge of the FKBP-12 gene structure will enable inactivation of this gene by homologous recombination in cells to provide a model to study the role of FKBP-12 in immunoregulation and normal cellular processes.
FKBP - 12是免疫抑制剂FK506和雷帕霉素的主要T细胞结合蛋白，它催化肽和蛋白质底物的肽基 - 脯氨酰胺键的顺式和反式旋转异构体的相互转化。旋转异构酶活性在细胞中的功能以及FKBP - 12在免疫调节中的作用尚不确定。在本文中，我们报告了人类染色体FKBP - 12基因和四个加工后的FKBP - 12假基因的克隆与特性。FKBP - 12基因长度为24千碱基，包含五个外显子。该基因的蛋白质编码区分为四个外显子模块，与蛋白质的结构和功能域相关。由反平行β折叠拓扑结构产生的FKBP - 12的新结构是由单独外显子编码的两个环的拓扑交叉。单独的外显子还编码定义FKBP - 12药物结合口袋和酶活性位点的反平行β折叠和α螺旋区域。FKBP - 12基因的外显子组织也为亲免素家族的遗传进化提供了见解。了解FKBP - 12基因结构将能够通过细胞中的同源重组使该基因失活，从而提供一个模型来研究FKBP - 12在免疫调节和正常细胞过程中的作用。
