SUMMARY PARAGRAPH for FPR1
FPR1 encodes a peptidyl-prolyl cis-trans isomerase that helps mediate correct protein folding (2). Fpr1p is a member of a large group of prolyl isomerases comprised of three structurally unrelated families: the FKBPs (FK506 binding proteins), the cyclophilins, and the parvulins (reviewed in 4). S. cerevisiae contains 4 FKBPs (Fpr1p, 2p, 3p, and 4p), 8 cyclophilins (Cpr1p through Cpr8p), and one parvulin (Ess1p; reviewed in 4).
Fpr1p can bind the related macrolides rapamycin and the immunosuppressant FK506; binding to either inhibits its peptidyl-prolyl isomerase activity and is toxic to yeast (2, 5). Toxicity is not due to inhibition of activity, however, because fpr1 null mutants are viable (6). Rather, toxicity is caused by interaction of the bound Fpr1p with signaling proteins: FK506-bound Fpr1p binds to calcineurin A subunit (isoforms Cmp2p and Cna1p) and exerts a negative regulatory role in calcineurin function, and rapamycin-bound Fpr1p binds directly to Tor1p and Tor2p, leading to G1 arrest (7, 8, 9, 10).
In the absence of macrolide binding, Fpr1p appears to regulate the homoserine biosynthetic pathway by perturbing feedback inhibition of aspartokinase by threonine (11). Endogenous Fpr1p (not bound to FK506 or rapamycin) interacts directly with aspartokinase (Hom3p), the first enzyme in the pathway that converts aspartate to either threonine or methionine (12). Loss of Fpr1p function causes resistance to the toxic amino acid analog hydroxynorvaline, a phenotype also observed in cells that synthesize a feedback-resistant form of aspartokinase, suggesting that Fpr1p regulates feedback inhibition of Hom3p (13, 12). Another target of Fpr1p is Hmo1p, a nonhistone, chromatin-binding protein of the high mobility group (HMG) family (3). Hmo1p forms homodimers or homooligomers, and Fpr1p plays a role in regulating this self-association (reviewed in 4).
Fpr1p homologs have been identified in the fungal pathogens C. neoformans and C. albicans, and in S. pombe (reviewed in 4). The human Fpr1p ortholog, FKBP12, is the intracellular receptor for FK506; the FKBP12-FK506 complex mediates immunosuppression through inhibition of calcineurin (reviewed in 4).
Last updated: 2008-12-09