Elucidation of a structural basis for the inhibitor-driven, p62 (SQSTM1)-dependent intracellular redistribution of cAMP phosphodiesterase-4A4 (PDE4A4)

Day, J. P. et al. (2011) Elucidation of a structural basis for the inhibitor-driven, p62 (SQSTM1)-dependent intracellular redistribution of cAMP phosphodiesterase-4A4 (PDE4A4). Journal of Medicinal Chemistry, 54(9), pp. 3331-3347. (doi:10.1021/jm200070e)

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Publisher's URL: http://dx.doi.org/10.1021/jm200070e


A survey of PDE4 inhibitors reveals that some compounds trigger intracellular aggregation of PDE4A4 into accretion foci through association with the ubiquitin-binding scaffold protein p62 (SQSTM1). We show that this effect is driven by inhibitor occupancy of the catalytic pocket and stabilization of a “capped state” in which a sequence within the enzyme’s upstream conserved region 2 (UCR2) module folds across the catalytic pocket. Only certain inhibitors cause PDE4A4 foci formation, and the structural features responsible for driving the process are defined. Switching to the UCR2-capped state induces conformational transition in the enzyme’s regulatory N-terminal portion, facilitating protein association events responsible for reversible aggregate assembly. PDE4-selective inhibitors able to trigger relocalization of PDE4A4 into foci can therefore be expected to exert actions on cells that extend beyond simple inhibition of PDE4 catalytic activity and that may arise from reconfiguring the enzyme’s protein association partnerships.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Houslay, Professor Miles and Baillie, Professor George and Christian, Dr Frank and Anthony, Dr Diana and Huston, Dr Elaine and Day, Dr Jonathan
Authors: Day, J. P., Lindsay, B., Riddell, T., Jiang, Z., Allcock, R. W., Abraham, A., Sookup, S., Christian, F., Bogum, J., Martin, E. K., Rae, R. L., Anthony, D., Rosair, G. M., Houslay, D. M., Huston, E., Baillie, G. S., Klussmann, E., Houslay, M. D., and Adams, D. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Journal of Medicinal Chemistry
Journal Abbr.:J. Med. Chem.
Publisher:American Chemical Society
ISSN (Online):1520-4804
Published Online:04 April 2011
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
438301Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targetsMiles HouslayMedical Research Council (MRC)G0600765Institute of Neuroscience and Psychology
432501Transatlantic networks of excellence in cardiovascular diseaseMiles HouslayFoundation Leducq (LEDUCQ-VIL)06 CVD 02Institute of Neuroscience and Psychology