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FAP1, a homologue of human transcription factor NF‐X1, competes with rapamycin for binding to FKBP12 in yeast
Author(s) -
Kunz Jeannette,
Loeschmann Andrea,
DeuterReinhard Maja,
Hall Michael N.
Publication year - 2000
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1046/j.1365-2958.2000.02105.x
Subject(s) - biology , fkbp , schizosaccharomyces pombe , transcription factor , prolyl isomerase , gene , caenorhabditis elegans , genetics , yeast , saccharomyces cerevisiae , microbiology and biotechnology , isomerase , pin1
The immunosuppressive drug rapamycin binds to the peptidyl‐prolyl cis‐trans isomerase FKBP12, and this complex arrests growth of yeast cells and activated T lymphocytes in the G1 phase of the cell cycle. In yeast, loss‐of‐function mutations in FPR1 , the gene encoding FKBP12, or dominant gain‐of‐function mutations in TOR1 and TOR2 , the genes encoding the physical targets of the FKBP12–rapamycin complex, confer rapamycin resistance. Here, we report the cloning and characterization of a novel gene, termed FAP1 , which confers resistance to rapamycin by competing with the drug for binding to FKBP12. FAP1 encodes a member of an evolutionarily conserved family of putative transcription factors that includes human NF‐X1, Drosophila melanogaster shuttle craft and previously undescribed homologues in Caenorhabditis elegans , Arabidopsis thaliana and Schizosaccharomyces pombe . We provide genetic and biochemical evidence that FAP1 interacts physically with FKBP12 in vivo and in vitro , and that it competes with rapamycin for interaction. Furthermore, mutations in the FKBP12 drug binding/active site or surface residues abolish binding to FAP1. Our results suggest that FAP1 is a physiological ligand for FKBP12 that is highly conserved from yeast to man. Furthermore, prolyl isomerases may commonly bind and regulate transcription factors.