ALL CYCLOPHILINS AND FK506 BINDING-PROTEINS ARE, INDIVIDUALLY AND COLLECTIVELY, DISPENSABLE FOR VIABILITY IN SACCHAROMYCES-CEREVISIAE

The cyclophilins and FK506 binding proteins (FKBPs) bind to cyclospori n A, FK506, and rapamycin and mediate their immunosuppressive and toxi c effects, but the physiological functions of these proteins are large ly unknown. Cyclophilins and FKBPs are ubiquitous and highly conserved enzymes that catalyze peptidyl-prolyl isomerization, a rate-limiting step during in vitro protein folding. We have addressed their function s by a genetic approach in the yeast Saccharomyces cerevisiae. Five cy clophilins and three FKBPs previously were identified in yeast. We ide ntified four additional enzymes: Cpr6 and Cpr7, which are homologs of mammalian cyclophilin 40 that have also recently been independently is olated by others, Cpr8, a homolog of the secretory pathway cyclophilin Cpr4, and Fpr4, a homolog of the nucleolar FKBP, Fpr3. None of the ei ght cyclophilins or four FKBPs were essential. Surprisingly, yeast mut ants lacking all 12 immunophilins were viable, and the phenotype of th e dodecuplet mutant resulted from simple addition of the subtle phenot ypes of each individual mutation. We conclude that cyclophilins and FK BPs do not play an essential general role in protein folding and find little evidence of functional overlap between the different enzymes. W e propose that each cyclophilin and FKBP instead regulates a restricte d number of unique partner proteins that remain to be identified.