RAFT1 - A MAMMALIAN PROTEIN THAT BINDS TO FKBP12 IN A RAPAMYCIN-DEPENDENT FASHION AND IS HOMOLOGOUS TO YEAST TORS

The immunosuppressants rapamycin and FK506 bind to the same intracellu lar protein, the immunophilin FKBP12. The FKBP12-FK506 complex interac ts with and inhibits the Ca2+-activated protein phosphatase calcineuri n. The target of the FKBP12-rapamycin complex has not yet been identif ied. We report that a protein complex containing 245 kDa and 35 kDa co mponents, designated rapamycin and FKBP12 targets 1 and 2 (RAFT1 and R AFT2), interacts with FKBP12 in a rapamycin-dependent manner. Sequence s (330 amino acids total) of tryptic peptides derived from the 245 kDa RAFT1 reveal striking homologies to the yeast TOR gene products, whic h were originally identified by mutations that confer rapamycin resist ance in yeast. A RAFT1 cDNA was obtained and found to encode a 289 kDa protein (2549 amino acids) that is 43% and 39% identical to TOR2 and TOR1, respectively. We propose that RAFT1 is the direct target of FKBP 12-rapamycin and a mammalian homolog of the TOR proteins.