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Molecular and Cellular Biology, October 2002, p. 6993-7003, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.6993-7003.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cyclophilin A Peptidyl-Prolyl Isomerase Activity Promotes Zpr1 Nuclear Export

Departments of Microbiology,¹ Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032²

Received 29 April 2002/ Returned for modification 3 July 2002/ Accepted 10 July 2002

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 cpr1 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 EF1 (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 cpr1 cells. Transport kinetic studies indicated that nuclear export of Zpr1p was defective in cpr1 cells, and rescue of this defect correlated with PPIase activity. Our results demonstrate a functional interaction between Cpr1p, Zpr1p, and EF1, a role for Cpr1p in Zpr1p nuclear export, and a biological function for Cpr1p PPIase activity.

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