Houslay, K. F., Christian, F. , MacLeod, R., Adams, D. R., Houslay, M. D. and Baillie, G. S. (2017) Identification of a multifunctional docking site on the catalytic unit of phosphodiesterase-4 (PDE4) that is utilised by multiple interaction partners. Biochemical Journal, 474(4), pp. 597-609. (doi: 10.1042/BCJ20160849) (PMID:27993970) (PMCID:PMC5290487)
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Abstract
Cyclic AMP (cAMP) specific phosphodiesterase-4 (PDE4) enzymes underpin compartmentalised cAMP signalling by localising to distinct signalling complexes. PDE4 long isoforms can be phosphorylated by mitogen-activated protein kinase-activated protein kinase 2 (MK2), which attenuates activation of such enzymes through their phosphorylation by protein kinase A (PKA). Here we show that MK2 interacts directly with PDE4 long isoforms and define the sites of interaction. One is a unique site that locates within the regulatory UCR1 domain and contains a core Phe141, Leu142 and Tyr143 (FLY) cluster (PDE4A5 numbering). Located with the second site is a critical core Phe693, Glu694, Phe695 (FQF) motif that is also employed in the sequestering of PDE4 long forms by an array of other signalling proteins, including the signalling scaffold beta-arrestin, the tyrosyl kinase Lyn, the SUMOylation E2 ligase UBC9, the dynein regulator Lis1 (PAFAH1B1) and the protein kinase Erk. We propose that the FQF motif lies at the heart of a multi-functional docking (MFD) site located within the PDE4 catalytic unit. It is clear from our data that, as well as aiding fidelity of interaction, the MFD site confers exclusivity of binding between PDE4 and a single specific partner protein from the cohort of signalling proteins whose interaction with PDE4 involves the FQF motif.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Baillie, Professor George and Houslay, Professor Miles and MacLeod, Miss Ruth and Christian, Dr Frank |
Authors: | Houslay, K. F., Christian, F., MacLeod, R., Adams, D. R., Houslay, M. D., and Baillie, G. S. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience |
Journal Name: | Biochemical Journal |
Publisher: | Portland Press Ltd. |
ISSN: | 0264-6021 |
ISSN (Online): | 1470-8728 |
Published Online: | 19 December 2016 |
Copyright Holders: | Copyright © 2017 The Authors |
First Published: | First published in Biochemical Journal 474(4): 597-609 |
Publisher Policy: | Reproduced under a Creative Commons License |
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