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J. Biol. Chem., Vol. 277, Issue 43, 40212-40221, October 25, 2002
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From the Division of Reproductive Biology, Department of Gynecology
and Obstetrics, Stanford University School of Medicine, Stanford,
California 94305-5317
The cAMP-specific PDE4 family consists of four
genes, each expressed as several splice variants. These variants are
termed long and short forms depending on the presence or absence of two unique N-terminal domains called upstream conserved regions 1 and 2 (UCR1 and 2). UCR1 and UCR2 have been shown to form a module necessary
for the activation of PDE4 upon phosphorylation by the cAMP-dependent kinase (PKA). Here we have uncovered PDE4
oligomerization as a novel function for the UCR1/UCR2 module. Using
several different approaches including gel filtration, sucrose density
gradient centrifugation, pull-down of differentially tagged PDE
constructs, and yeast two-hybrid assay, we show that the long PDE4
splice variant PDE4D3 behaves as a dimer, whereas the short splice
variant PDE4D2 is a monomer. Internal deletions of either the
C-terminal portion of UCR1 or the N-terminal portion of UCR2 abolishes
dimerization of PDE4D3 indicating that both domains are involved in
this intermolecular interaction. The dimerization, however, is
structurally distinguishable from a previously described intramolecular
interaction involving the same domains. PKA phosphorylation and
site-directed mutagenesis shown to ablate the latter do not interfere
with dimerization. Therefore, dimerization of the long PDE4
forms may be an additional function of the UCR domains that further
explains differences in the regulatory properties between the long and
short PDE4 splice variants.
Dimerization of the Type 4 cAMP-specific Phosphodiesterases Is
Mediated by the Upstream Conserved Regions (UCRs)*
*
This work was supported by National Institutes of Health
Grant HD20788 (to M. C.) and a fellowship grant from the German
Academic Exchange Service (to W. R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of
Reproductive Biology, Dept. of Gynecology and Obstetrics, Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA
94305-5317. Tel.: 650-725-2452; Fax: 650-725-7102; E-mail:
marco.conti@stanford.edu.
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