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Papers In Press, published online ahead of print June 16, 2003
Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294-3300
Corresponding Author: Graeme.Bolger{at}ccc.uab.edu
The cyclic AMP-specific phosphodiesterase (PDE4) isoform PDE4A5 interacted with the immunophilin XAP2 in a yeast two-hybrid assay. The interaction was confirmed in biochemical pull-down analyses. The interaction was specific, in that PDE4A5 did not interact with the closely-related immunophilins AIPL1, FKBP51 or FKBP52. XAP2 also did not interact with other PDE4A isoforms or typical isoforms from the three other PDE4 subfamilies. Functionally, XAP2 reversibly inhibited the enzymatic activity of PDE4A5, increased the sensitivity of PDE4A5 to inhibition by the prototypical PDE4 inhibitor rolipram and attenuated the ability of cAMP-dependent protein kinase to phosphorylate PDE4A5 in intact cells. XAP2 maximally inhibited PDE4A5 by approximately 60%, with an IC50 of 120 nM, and reduced the IC50 for rolipram from 390 nM to 70-90 nM. Co-expression of XAP2 and PDE4A5 in COS7 cells showed that they could be co-immunoprecipitated and also reduced both the enzymatic activity of PDE4A5 and its IC50 for rolipram. Native XAP2 and PDE4A5 could be co-immunoprecipitated from brain. The isolated C-terminal half of XAP2 (amino acids 170-330), containing its tetratricopeptide repeat (TPR) domain, but not the isolated N-terminal half (amino acids 1-169), containing the immunophilin homology region, similarly reduced PDE4A5 activity and its IC50 for rolipram. Mutation of R271 to alanine, in the XAP2 TPR region, attenuated its ability to both interact with PDE4A5 in two-hybrid assays and to inhibit PDE4A5 activity. Either the deletion of a specific portion of the unique amino-terminal region, or specific mutations in the regulatory UCR2 domain, of PDE4A5 attenuated its ability be inhibited by XAP2. We suggest that XAP2 functionally interacts with PDE4A5 in cells.
J. Biol. Chem, 10.1074/jbc.M303269200
Submitted on March 30, 2003
Revised on May 28, 2003
Accepted on June 16, 2003
Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2
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