PDE4s (type 4 cyclic nucleotide phosphodiesterases) are divided into long and short forms by the presence or absence of conserved N-terminal domains termed UCRs (upstream conserved regions). We have shown previously that PDE4D2, a short variant, is a monomer, whereas PDE4D3, a long variant, is a dimer. In the present study, we have determined the apparent molecular masses of various long and short PDE4 variants by size-exclusion chromatography and sucrose density-gradient centrifugation. Our results indicate that dimerization is a conserved property of all long PDE4 forms, whereas short forms are monomers. Dimerization is mediated by the UCR domains. Given their high sequence conservation, the UCR domains mediate not only homo-oligomerization, but also hetero-oligomerization of distinct PDE4 long forms as detected by co-immunoprecipitation assays and FRET microscopy. Endogenous PDE4 hetero-oligomers are, however, low in abundance compared with homo-dimers, revealing the presence of mechanisms that predispose PDE4s towards homo-oligomerization. Oligomerization is a prerequisite for the regulatory properties of the PDE4 long forms, such as their PKA (protein kinase A)-dependent activation, but is not necessary for PDE4 protein–protein interactions. As a result, individual PDE4 protomers may independently mediate protein–protein interactions, providing a mechanism whereby PDE4s contribute to the assembly of macromolecular signalling complexes.
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Research Article|
April 11 2014
The upstream conserved regions (UCRs) mediate homo- and hetero-oligomerization of type 4 cyclic nucleotide phosphodiesterases (PDE4s)
Moses Xie;
Moses Xie
1
*Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, U.S.A.
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Brigitte Blackman;
Brigitte Blackman
*Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, U.S.A.
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Colleen Scheitrum;
Colleen Scheitrum
*Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, U.S.A.
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Delphine Mika;
Delphine Mika
*Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, U.S.A.
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Elise Blanchard;
Elise Blanchard
*Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, U.S.A.
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Tao Lei;
Tao Lei
*Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, U.S.A.
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Marco Conti;
Marco Conti
*Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, U.S.A.
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Wito Richter
Wito Richter
2
*Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94143, U.S.A.
2To whom correspondence should be addressed (email richterw@obgyn.ucsf.edu).
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Publisher: Portland Press Ltd
Received:
December 20 2013
Revision Received:
February 18 2014
Accepted:
February 21 2014
Accepted Manuscript online:
February 21 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 459 (3): 539–550.
Article history
Received:
December 20 2013
Revision Received:
February 18 2014
Accepted:
February 21 2014
Accepted Manuscript online:
February 21 2014
Citation
Moses Xie, Brigitte Blackman, Colleen Scheitrum, Delphine Mika, Elise Blanchard, Tao Lei, Marco Conti, Wito Richter; The upstream conserved regions (UCRs) mediate homo- and hetero-oligomerization of type 4 cyclic nucleotide phosphodiesterases (PDE4s). Biochem J 1 May 2014; 459 (3): 539–550. doi: https://doi.org/10.1042/BJ20131681
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