All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae

Abstract

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.Cyclophilin A and FKBP12 originally were isolated as cyclosporin A (CsA) and FK506 binding proteins (FKBPs) and later shown to inhibit the calcium͞calmodulin-dependent serine͞threonine phosphatase, calcineurin, as protein-drug complexes (reviewed in refs.

Hsp90—From signal transduction to cell transformation

“…A number of TPR-containing co-chaperones even convey their own catalytic activities [5]. These include such enzymes as the E3/E4-ubiquitin ligase, CHIP [31], the protein phosphatase, PP5 [32], and several prolyl isomerases [33,34]. It is known that CHIP functions in the targeting of Hsp90 client proteins for proteasome-mediated degradation [31].…”

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

“…FKBP12 is an abundant and ubiquitously expressed peptidyl-prolyl cis/trans isomerase that may function in protein folding (reviewed in Schreiber, 1991). While rapamycin inhibits the isomerase activity of FKBP12 (Heitman et al, 1991;Koltin et al, 1991;Wiederrecht et al, 1991), it appears that inhibition of this activity is not responsible for rapamycin sensitivity: Deletion of FPR1 (FKBP12) (or deletion of all four FKBP12 genes (FPR1-4)) in S. cerevisiae is not lethal; rather, the yeast are viable and exhibit resistance to the toxic effects of rapamycin (Heitman et al, 1991;Koltin et al, 1991;Dolinski et al, 1997). Therefore, it is the presence of FKBP12, not its activity, that is required for the toxic, antiproliferative action of rapamycin in yeast.…”

Structure-Function Analysis of PrsA Reveals Roles for the Parvulin-like and Flanking N- and C-terminal Domains in Protein Folding and Secretion in Bacillus subtilis

“…Although PPIases catalyze the isomerization of prolyl peptide bonds in vitro, the physiological role of many of these proteins is still unclear. The effects of their mutational inactivation vary from no phenotypic effect (2) to severe defects (3)(4)(5)(6). PPIases may also act as chaperones either in a PPIase domain-dependent (7) or -independent (8) manner, and they may have essential overlapping functions with other PPIases and chaperones (4,9,10).…”