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Papers In Press, published online ahead of print May 6, 2004
Department of Gynecology and Obstetrics, Stanford University, Stanford, CA 94305-5317
Corresponding Author: marco.conti{at}stanford.edu
PDE4 splice variants are classified into long and short forms depending on the presence or absence of two unique N-terminal domains termed upstream conserved regions 1 and 2 (UCR1 and 2). We have shown previously that the UCR module mediates dimerization of PDE4 long forms whereas short forms, which lack UCR1, behave as monomers. In the present study, we demonstrate that dimerization is an essential structural element that determines the regulatory properties and inhibitor sensitivities of PDE4 enzymes. Comparing the properties of the dimeric wild type PDE4D3 with several monomeric mutant-PDE4D3 constructs revealed that disruption of dimerization ablates the activation of PDE4 long forms by either PKA phosphorylation or phosphatidic acid binding. In addition, the analysis of heterodimers consisting of a catalytically active and a catalytically inactive PDE4D3 subunit indicates that PKA phosphorylation of both subunits is essential to fully activate PDE4 enzymes. In addition to affecting enzyme regulation, disruption of dimerization reduces the sensitivity of the enzymes towards the prototypical PDE4 inhibitor, Rolipram. Parallel binding assays indicated that this shift in Rolipram sensitivity is likely mediated by a decrease in the number of inhibitor binding sites in the High Affinity Rolipram Binding State (HARBS). Thus, although dimerization is not a requirement for high affinity Rolipram binding, it functions to stabilize PDE4 long forms in their HARBS conformation. Taken together, our data indicate that dimerization defines the properties of PDE4 enzymes and suggest a common structural and functional organization for all PDEs.
J. Biol. Chem, 10.1074/jbc.M312687200
Submitted on November 20, 2003
Revised on April 23, 2004
Accepted on May 6, 2004
The oligomerization state determines regulatory properties and inhibitor sensitivity of type 4 cAMP-specific phosphodiesterases
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