Cyclophilin A peptidyl-prolyl isomerase activity promotes ZPR1 nuclear export.
The peptidyl-prolyl isomerase (PPIase) cyclophilin A (Cpr1p) is conserved from eubacteria to mammals, yet its biological function has resisted elucidation. Unable to identify a phenotype that is suggestive of Cpr1p's function in a cpr1Delta Saccharomyces cerevisiae strain, we screened for CPR1-dependent strains. In all cases, dependence was conferred by mutations in ZPR1, a gene encoding an essential zinc finger protein. CPR1 dependence was suppressed by overexpression of EF1alpha (a translation factor that binds Zpr1p), Cpr6p (another cyclophilin), or Fpr1p (a structurally unrelated PPIase). Suppression by a panel of cyclophilin A mutants correlated with PPIase activity, confirming the relevance of this activity in CPR1-dependent strains. In CPR1(+) cells, wild-type Zpr1p was distributed equally between the nucleus and cytoplasm. In contrast, proteins encoded by CPR1-dependent alleles of ZPR1 accumulated in the nucleus, as did wild-type Zpr1p in cpr1Delta cells. Transport kinetic studies indicated that nuclear export of Zpr1p was defective in cpr1Delta cells, and rescue of this defect correlated with PPIase activity. Our results demonstrate a functional interaction between Cpr1p, Zpr1p, and EF1alpha, a role for Cpr1p in Zpr1p nuclear export, and a biological function for Cpr1p PPIase activity.
Ansari
Husam
H
Departments of Microbiology. Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Greco
Giampaolo
G
Luban
Jeremy
J
D021581:Active Transport, Cell Nucleus; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D016296:Mutagenesis; D020648:Peptide Elongation Factor 1 / Q000235:genetics / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010957:Plasmids; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D016335:Zinc Fingers
D002352:Carrier Proteins; D000081406:Peptidyl-Prolyl Isomerase F; D020648:Peptide Elongation Factor 1; D029701:Saccharomyces cerevisiae Proteins; C490986:ZPR1 protein, S cerevisiae; D021984:Cyclophilin A; D021983:Cyclophilins; D019696:Peptidylprolyl Isomerase