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 cyclosporin A, FK506, and rapamycin and mediate their immunosuppressive and toxic effects, but the physiological functions of these proteins are largely 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 functions by a genetic approach in the yeast Saccharomyces cerevisiae. Five cyclophilins and three FKBPs previously were identified in yeast. We identified four additional enzymes: Cpr6 and Cpr7, which are homologs of mammalian cyclophilin 40 that have also recently been independently isolated by others, Cpr8, a homolog of the secretory pathway cyclophilin Cpr4, and Fpr4, a homolog of the nucleolar FKBP, Fpr3. None of the eight cyclophilins or four FKBPs were essential. Surprisingly, yeast mutants lacking all 12 immunophilins were viable, and the phenotype of the dodecuplet mutant resulted from simple addition of the subtle phenotypes of each individual mutation. We conclude that cyclophilins and FKBPs do not play an essential general role in protein folding and find little evidence of functional overlap between the different enzymes. We propose that each cyclophilin and FKBP instead regulates a restricted number of unique partner proteins that remain to be identified.
Dolinski
K
K
Department of Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Muir
S
S
Cardenas
M
M
Heitman
J
J
D000595:Amino Acid Sequence; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics*; D018869:Heat-Shock Response; D056488:Histone Chaperones; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000235:genetics*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D056488:Histone Chaperones; D029701:Saccharomyces cerevisiae Proteins; D022021:Tacrolimus Binding Proteins; C513494:Fpr4 protein, S cerevisiae; D019696:Peptidylprolyl Isomerase