title: Elucidation of a structural basis for the inhibitor-driven, p62 (SQSTM1)-dependent intracellular redistribution of cAMP phosphodiesterase-4A4 (PDE4A4).
abstract: 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.
authors: Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
authors: Jonathan P
authors: JP
authors: Day
authors: Barbara
authors: B
authors: Lindsay
authors: Tracy
authors: T
authors: Riddell
authors: Zhong
authors: Z
authors: Jiang
authors: Robert W
authors: RW
authors: Allcock
authors: Achamma
authors: A
authors: Abraham
authors: Sebastian
authors: S
authors: Sookup
authors: Frank
authors: F
authors: Christian
authors: Jana
authors: J
authors: Bogum
authors: Elisabeth K
authors: EK
authors: Martin
authors: Robert L
authors: RL
authors: Rae
authors: Diana
authors: D
authors: Anthony
authors: Georgina M
authors: GM
authors: Rosair
authors: Daniel M
authors: DM
authors: Houslay
authors: Elaine
authors: E
authors: Huston
authors: George S
authors: GS
authors: Baillie
authors: Enno
authors: E
authors: Klussmann
authors: Miles D
authors: MD
authors: Houslay
authors: David R
authors: DR
authors: Adams
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D016466:CHO Cells; D020134:Catalytic Domain; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D020889:Rolipram / Q000737:chemistry / Q000494:pharmacology; D000071456:Sequestosome-1 Protein; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000737:chemistry / Q000494:pharmacology; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007527:Isoenzymes; D058988:Phosphodiesterase 4 Inhibitors; D011725:Pyridines; D020889:Rolipram; D000071456:Sequestosome-1 Protein; D013141:Spiro Compounds; D014970:Xanthines; C099718:SQSTM1 protein, human; C466758:cipamfylline; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles