2. Academic Validation
  3. A cyclophilin functions in pre-mRNA splicing

A cyclophilin functions in pre-mRNA splicing

  • EMBO J. 2002 Feb 1;21(3):470-80. doi: 10.1093/emboj/21.3.470.
David S Horowitz 1,  Edward J Lee,  Stephen A Mabon,  Tom Misteli
Affiliations

Affiliation

  • 1 Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. dhorowitz@usuhs.mil
PMID: 11823439 DOI: 10.1093/emboj/21.3.470
Abstract

We report that the Cyclophilin USA-CyP is part of distinct complexes with two spliceosomal proteins and is involved in both steps of pre-mRNA splicing. The splicing factors hPrp18 and hPrp4 have a short region of homology that defines a high affinity binding site for USA-CyP in each protein. USA-CyP forms separate, stable complexes with hPrp18 and hPrp4 in which the active site of the Cyclophilin is exposed. The Cyclophilin Inhibitor cyclosporin A slows pre-mRNA splicing in vitro, and we show that its inhibition of the second step of splicing is caused by blocking the action of USA-CyP within its complex with hPrp18. Cyclosporin A also slows splicing in vivo, and we show that this slowing results specifically from inhibition of USA-CyP. Our results lead to a model in which USA-CyP is carried into the spliceosome in complexes with hPrp4 and hPrp18, and USA-CyP acts during splicing within these complexes. These results provide an example of the function of a Cyclophilin in a complex process and provide insight into the mechanisms of action of cyclophilins.

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