Exon organization of the human FKBP-12 gene: correlation with structural and functional protein domains.
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.
DiLella
A G
AG
Department of Molecular Genetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
Craig
R J
RJ
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D004247:DNA / Q000737:chemistry; D015342:DNA Probes; D005091:Exons; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry*; D008969:Molecular Sequence Data; D011090:Polyenes / Q000737:chemistry*; D011487:Protein Conformation; D011544:Pseudogenes; D020123:Sirolimus; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000737:chemistry / Q000378:metabolism; D016559:Tacrolimus; D022021:Tacrolimus Binding Proteins
D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D015342:DNA Probes; D007166:Immunosuppressive Agents; D011090:Polyenes; D004247:DNA; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D016559:Tacrolimus